The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index; 22 of the 57 sources its claims cite were checked for support.
The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling
Open accessAbstract
Negative feedback is a mechanism commonly employed in biological processes as a means of maintaining homeostasis. We have investigated the roles of suppressor of cytokine signaling (SOCS) proteins in regulating the kinetics of negative feedback in response to cytokine signaling. In mouse livers and bone marrow-derived macrophages, both interferon-gamma (IFNgamma) and interleukin-6 (IL-6) rapidly induced the tyrosine phosphorylation of signal transducer and activator of transcription-1 (STAT1) and STAT3. STAT3 tyrosine phosphorylation was bi-phasic in response to continuous IL-6 signaling. In macrophages lacking Socs3, however, continuous IL-6 signaling induced uniformly high levels of STAT3 tyrosine phosphorylation, and early IL-6-inducible genes were inappropriately expressed at intermediate time points. SOCS3 therefore imposes bi-phasic kinetics upon IL-6 signaling. Compared with Socs3 mRNA, Socs1 mRNA was induced relatively slowly, and SOCS1 simply attenuated the duration of IFNgamma signaling. Surprisingly, heightened Socs1 mRNA expression but minimal STAT1 tyrosine phosphorylation was observed after prolonged stimulation with IFNgamma, indicating that STAT1 may not play a large role in inducing Socs1 mRNA during steady-state IFNgamma signaling. We also demonstrate that both SOCS1 and SOCS3 can desensitize primary bone marrow-derived macrophages to IFNgamma and IL-6 signaling, respectively. Consistent with the kinetics with which Socs1 and Socs3 mRNAs were induced, SOCS3 desensitized cells to IL-6 rapidly, whereas SOCS1-mediated desensitization to IFNgamma occurred at later time points. The kinetics with which SOCS proteins are induced by cytokine may therefore be a parameter that is "hard-wired" into specific cytokine signaling pathways as a means of tailoring the kinetics with which cells become desensitized.
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TL;DR
This study compares SOCS1 and SOCS3 in IFNγ and IL-6 signaling, showing SOCS3 imposes bi-phasic STAT3 kinetics and rapid desensitization to IL-6, whereas SOCS1 slowly attenuates IFNγ signaling and desensitizes cells later. Both SOCS proteins can desensitize primary macrophages, with induction kinetics tailored to the cytokine.
Key findings
- In mouse livers, IFNγ and IL-6 rapidly induced STAT1/STAT3 tyrosine phosphorylation; STAT3 phosphorylation declined to near basal by 4 h, while STAT1 phosphorylation declined by 4 h after IFNγ but by only 1 h after IL-6. SOCS1 protein peaked at 2–4 h after IFNγ and was maintained for at least 8 h; SOCS3 protein peaked at 30 min–1 h after IL-6, and IFNγ induced barely detectable SOCS3.
- In bone marrow-derived macrophages, continuous IL-6 produced bi-phasic STAT3 phosphorylation: first between 15–30 min and second from 120 min onward. Socs3 mRNA peaked at 30 min, was minimal at 60–90 min, and re-established by 180 min. In Socs3−/Δ macrophages, STAT3 phosphorylation remained high, and IL-6-inducible Gadd45γ and Ttp were sustained or heightened.
- SOCS1 effects on STAT1 phosphorylation were not apparent until ~90 min after IFNγ, ~60 min later than SOCS3 effects in IL-6. Socs1 mRNA was induced slowly but remained near-maximal from 60 min to at least 480 min despite low STAT1 phosphorylation after 240 min. Both Socs1 and Socs3 mRNAs had a half-life of ~30 min.
- Both SOCS3 and SOCS1 desensitized macrophages to repeated IL-6 or IFNγ, respectively. SOCS3-mediated desensitization to IL-6 occurred rapidly (after 60, 90, 120, and 240 min), whereas SOCS1-mediated desensitization to IFNγ occurred at 120 min and later; limited desensitization to IL-6 remained in Socs3-deficient cells.
Methods
- C57BL/6 mice were injected with saline, IL-6 (500 µg/kg), or IFNγ (250 µg/kg); livers were collected over a 16-h time course for immunoprecipitation/Western blotting and real-time PCR.
- Primary bone marrow-derived macrophages from C57BL/6, Socs3−/Δ, Ifnγ−/−, and Socs1−/−Ifnγ−/− mice were stimulated with IL-6 (250 ng/ml) or IFNγ (125 ng/ml), including pulsed stimulations and actinomycin-D treatment for mRNA stability assays.
- Microarray time-course analysis used MGU74Av2 GeneChips with livers from Ifnγ−/− and Ifnγ−/−Socs1−/− mice; genes changed >1.7-fold over two consecutive samples were clustered with GeneCluster2, and Q-PCR was normalized to Pbgd.
Limitations
- The paper states that in vivo liver responses came from a single cytokine injection, whereas macrophage experiments used continuous stimulation, which may explain differences between systems. It also notes that microarray analysis used only a single liver per time point, and some gene clusters were variable and not specifically IFNγ-regulated.
- The paper states that the specific role of SOCS1 in desensitizing cells to IFNγ at later times is difficult to clarify because other factors, such as SHP-2 or T-cell protein-tyrosine phosphatase, also contribute. It also notes that Socs3-deficient hepatocytes and mouse embryonic fibroblasts showed basal STAT3 activation, limiting their use.
- Evident from the text: SOCS protein half-lives are inferred from mRNA and protein kinetics rather than directly measured, and desensitization in Socs3-deficient cells still showed limited IL-6 desensitization, indicating additional SOCS3-independent mechanisms.
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Claims the paper makes
60 Own result · 30 Own interpretation · 7 Supported · 7 Partly supported · 7 Own method · 6 Supported so far · 5 No full text of the sources · 4 No basis given · 2 Sources not found · 2 Not checked yet · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“SOCS1 and SOCS3 proteins can both inhibit JAK phosphorylation of STAT, thus creating a negative feedback loop that attenuates cytokine signal transduction, although the mechanisms by which they act appear to differ.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Abstract
What the sources say
- Not checked — no full text of the sourcecites [19] Endo, 1997, Nature source
- Partly supportedcites [20] Nicholson, 1999, EMBO J. sourceExperimental — accuracy not yet measured
The section on STAT3 tyrosine phosphorylation reports that both SOCS-1 and SOCS-3 inhibit LIF-induced STAT3 phosphorylation in M1 cells. The Introduction describes a negative feedback loop for SOCS-1 only, not SOCS-3; the discussion (p. 382) also says SOCS-3 did not directly inhibit JAK kinase activity in the assay. Thus the shared reduction in STAT3 phosphorylation is supported, but a negative feedback loop for both proteins—and direct JAK inhibition by both—is not established. (LLM, conf=0.84)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Whereas SOCS1 functions by binding directly to JAK proteins, SOCS3 inhibits signaling by binding to phosphorylated tyrosine sites on the cytoplasmic domain of the receptor (19,20).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Abstract
What the sources say
- Not checked — no full text of the sourcecites [19] Endo, 1997, Nature source
- Supportedcites [20] Nicholson, 1999, EMBO J. source
The section on SOCS-1 inhibition of JAK kinase activity reports that full-length SOCS-1 coimmunoprecipitated with JAK1 and JAK2. The discussion (p. 382) also describes SOCS-1 domains interacting with JAK and contributing to inhibition of its kinase activity, supporting the attributed mechanism. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Every source the paper cites for this claim was checked and supports it.
In the paper
“Mice lacking Socs3 die during embryogenesis (23);”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Abstract
What the sources say
- Supportedcites [23] Roberts, 2001, Proc. Natl. Acad. Sci. U. S. A. source
The Results section reports that SOCS3-deficient embryos died between embryonic days E11 and E13. The Discussion likewise states that SOCS3 is essential for survival during embryogenesis. (LLM, conf=0.95)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Whereas SOCS1 functions by binding directly to JAK proteins, SOCS3 inhibits signaling by binding to phosphorylated tyrosine sites on the cytoplasmic domain of the receptor (19,20).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Abstract
What the sources say
- Not checked — no full text of the sourcecites [19] Endo, 1997, Nature source
- Partly supportedcites [20] Nicholson, 1999, EMBO J. sourceExperimental — accuracy not yet measured
The discussion (p. 382) says SOCS-3 inhibits IL-6 and LIF signaling, but presents binding to receptor phosphotyrosine residues as one possible mechanism, not an established one. The citing sentence states that mechanism as fact. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Every source the paper cites for this claim was checked and supports it.
In the paper
“STAT3 activates the transcription of Socs3 mRNA by associating with the 5Ј promoter region of the Socs3 gene (17).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Abstract
What the sources say
- Supportedcites [17] Auernhammer, 1999, Proc. Natl. Acad. Sci. U. S. A. source
The Discussion reports that murine SOCS-3 promoter activity depends on a STAT-1/STAT-3 binding element in its 5′ region. It also reports STAT-3 binding there and describes SOCS-3 expression as stimulated through a STAT-3-dependent pathway. The experiments concern LIF-stimulated expression in corticotroph cells, with STAT-1 also implicated. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Bi-phasic STAT3 activation has been reported in response to a variety of stimuli, including granulocyte-colony stimulating factor (37), leukemia inhibitory factor (38), IL-6 (27,38), and lipopolysaccharide (39).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > FIGURE 8. Desensitization of IL-6 and IFN␥ signaling by SOCS proteins.
What the sources say
- Not checked — no full text of the sourcecites [37] Steinman, 1999, Leukemia source
- Supportedcites [38] Wu, 1996, J. Biol. Chem. source
The citation to this paper is attached to IL-6, not to the other listed stimuli. The Discussion explicitly reports biphasic Stat3 activation after IL-6 treatment in PC12 cells; the supplied passage does not specify a page. (LLM, conf=0.94)
- Not checked — no full text of the sourcecites [39] Cowan, 2000, Am. J. Physiol. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Every source the paper cites for this claim was checked and supports it.
In the paper
“Consistent with previous observations (30), STAT1 tyrosine phosphorylation in response to IFN␥ was prolonged in the absence of SOCS1 (Fig. 4A).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > SOCS3 Is Responsible for Bi-phasic Tyrosine Phosphorylation of STAT3 and Expression of Genes in
What the sources say
- Supportedcites [30] Brysha, 2001, J. Biol. Chem. source
The section “IFNγ-induced STAT Activation Is Prolonged in Mice” reports that, after IFNγ injection, STAT1 phosphorylation persisted until 8 hours in mice lacking SOCS-1 but returned to basal levels by 4 hours in controls. The Figure 2 caption identifies the measured response as IFNγ-induced STAT1 phosphorylation. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“probably a result of the activity of the phosphatase SHP-2 (36).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > SOCS1 Desensitizes Bone Marrow-derived Macrophages to Repeated
What the sources say
- Partly supportedcites [36] You, 1999, Mol. Cell Biol. sourceExperimental — accuracy not yet measured
The Discussion identifies SHP-2 as a negative regulator of IFN-induced STAT signaling, including responses to IFN-γ. But the Results study fibroblasts and measure signaling at 5–60 minutes; they do not establish that SHP-2 causes desensitization at 240 minutes in Socs1-/- Ifnγ-/- macrophages. (LLM, conf=0.87)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Tyrosine phosphorylation of STAT proteins is a valid measure of cytokine signaling and desensitization.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“We initially examined IL-6 signaling in Socs3deficient primary hepatocytes, but like Socs3-deficient mouse embryonic fibroblasts (27), these cells exhibited signs of basal STAT3 activation (albeit to a lesser extent), including low level STAT3 tyrosine phosphorylation and induction of IL-6-inducible genes (data not shown).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Differential Induction of STAT1 and STAT3 Tyrosine Phosphorylation by IFN␥ and IL-6 in the
What the sources say
- Supportedcites [27] Fischer, 2004, Biochem. J. source
The citation (27) is attached to the comparison with SOCS3-deficient mouse embryonic fibroblasts, not to the citing authors’ observations in primary hepatocytes. In “Desensitization in SOCS3-deficient cells” (Figure 8B; page not provided), the source reports constitutively active STAT3 in SOCS3-deficient fibroblasts even without IL-6 stimulation. (LLM, conf=0.91)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“However, previous attempts to detect SOCS3-mediated desensitization of cytokine signaling in Socs3-deficient mouse embryonic fibroblasts were hampered by the constitutive activation of STAT3 in these cells (27).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > SOCS3 Desensitizes Bone Marrow-derived Macrophages to
What the sources say
- Supportedcites [27] Fischer, 2004, Biochem. J. source
In “Desensitization in SOCS3-deficient cells” (Figure 8), the authors report that SOCS3-deficient mouse embryonic fibroblasts had constitutively active STAT3 and that no desensitization could be observed after IL-6 pre-stimulation. This supports the citing sentence’s description of why the experiment could not reveal desensitization; the tested signaling was specifically IL-6 signaling. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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- Supported
- It may state two separate claims as one. 39
- Probably not a substantial claim. 8
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Surprisingly, IL-6 signaling in the absence of SOCS3 resulted in the prolonged phosphorylation of STAT1 and a qualitative shift in the transcriptional response of IL-6 toward that typical of IFN␥ (16,24,25).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Abstract
What the sources say
- Supportedcites [16] Wormald, 2003, J. Biol. Chem. source
The SOCS section reports prolonged IL-6-induced STAT1 activation in hepatocytes and macrophages lacking SOCS3, together with induction of genes normally associated with IFNγ signaling. Its pathway description explains that STAT activation involves phosphorylation, supporting the citing sentence’s paraphrase. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites [24] Croker, 2003, Nat. Immunol. source
- Not checked — no full text of the sourcecites [25] Lang, 2003, Nat. Immunol. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Both IFN␥ and IL-6 can activate JAK1 (4 -6) and JAK2 (7-10), and subsequently STAT1 (11,12) and STAT3 (6,13,14).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Abstract
What the sources say
- Not checked — no full text of the sourcecites [4] Kaplan, 1996, J. Biol. Chem. source
- Partly supportedcites [5] Greenlund, 1994, EMBO J. sourceExperimental — accuracy not yet measured
The Discussion reports that IFNγ rapidly activates JAK1 and JAK2, and the section on Y440 phosphorylation reports IFNγ-induced activation of p91. The paper mentions IL-6 receptor phosphorylation but does not establish that IL-6 activates JAK1, JAK2, STAT1, or STAT3; it also does not report STAT3 activation by IFNγ. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [6] Lutticken, 1994, Science source
- Not checked — no full text of the sourcecites [7] Kotenko, 1995, J. Biol. Chem. source
- Partly supportedcites [8] Bach, 1996, Mol. Cell Biol. sourceExperimental — accuracy not yet measured
The paper’s main-text excerpt (passage [5]; section and page not supplied) links IFNγ receptor signaling to JAK2 recruitment, supporting the IFNγ–JAK2 part of the cited statement. It does not establish IL-6 activation of JAK2. The citations attached to JAK1, STAT1, and STAT3 in the citing sentence are separate from this source’s citation to JAK2. (LLM, conf=0.85)
- Not checked — no full text of the sourcecites [9] Stahl, 1994, Science source
- Not checked — no full text of the sourcecites [10] Narazaki, 1994, Proc. Natl. Acad. Sci. U. S. A. source
- Not checked — no full text of the sourcecites [11] Shuai, 1993, Science source
- Not checked — no full text of the sourcecites [12] Harroch, 1994, J. Biol. Chem. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“This indicates that signaling by IFN␥ and IL-6 is fundamentally similar, and that the activity of SOCS3 is required to sculpt the cellular response to IL-6 and thereby discriminate it from that of IFN␥.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Abstract
What the sources say
- Partly supportedcites [16] Wormald, 2003, J. Biol. Chem. sourceExperimental — accuracy not yet measured
The SOCS section (page not supplied) reports that IL-6 induced IFNγ-associated genes in cells lacking SOCS3 and says SOCS3 plays an important role in sculpting the IL-6 response. It does not establish that IFNγ and IL-6 signaling are fundamentally similar or that SOCS3 is required to distinguish their responses; it says the exact nature of SOCS3’s role remains undetermined. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [24] Croker, 2003, Nat. Immunol. source
- Not checked — no full text of the sourcecites [25] Lang, 2003, Nat. Immunol. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In the case of IFN␥ signaling, the T-cell protein-tyrosine phosphatase has been shown to potently desensitize cells to repeated stimulation (28).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Abstract
What the sources say
- Partly supportedcites [28] Sakamoto, 2004, J. Biol. Chem. sourceExperimental — accuracy not yet measured
The Results passages describing Figs. 5–6 show reduced IFNγ-induced Stat1 activation after IFNβ pretreatment and implicate Tc-PTP in enhanced Stat1 dephosphorylation. They do not show desensitization caused by repeated IFNγ stimulation; the prior exposure was to IFNβ. Page numbers are not available in our copy. (LLM, conf=0.88)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The phosphorylated STATs (P-STATs) then dimerize and are transported to the nucleus, where they bind to promoter sequences, and activate the transcription of a suite of genes, among which are those encoding the suppressor of cytokine signaling-1 (SOCS1) and SOCS3 proteins (15,16).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Abstract
What the sources say
- Not checked — no full text of the sourcecites [15] Starr, 1997, Nature source
- Partly supportedcites [16] Wormald, 2003, J. Biol. Chem. sourceExperimental — accuracy not yet measured
The Fig. 1 caption (Conclusions; page unavailable) says phosphorylated STATs dimerize, enter the nucleus, and induce transcription of cytokine-regulated genes. The SOCS section suggests STAT3-mediated induction of SOCS3, and the PIAS section describes STAT association with DNA. Our copy does not specifically say that STATs bind promoter sequences or activate transcription of SOCS1. (LLM, conf=0.84)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Despite the physiologically distinct functions of IFN␥ and IL-6, the signaling mechanisms by which they elicit their cellular responses are similar, and in the case of IL-6 are distinguished at least in part through the activity of SOCS3 (16,24,25).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > DISCUSSION
What the sources say
- Supportedcites [16] Wormald, 2003, J. Biol. Chem. source
The SOCS section reports that IL-6 activates STAT1 and STAT3 and that, without SOCS3, IL-6 induces genes normally associated with IFNγ signaling. It concludes that SOCS3 helps shape the cellular response to IL-6, supporting the claim that SOCS3 contributes to the distinction between their responses. Page numbers are unavailable in our copy. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [24] Croker, 2003, Nat. Immunol. source
- Not checked — no full text of the sourcecites [25] Lang, 2003, Nat. Immunol. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“In contrast to the bi-phasic manner in which IL-6 signaling was regulated by SOCS3, IFN␥ signaling was simply attenuated in duration by SOCS1, a finding consistent with previous observations (30).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > FIGURE 8. Desensitization of IL-6 and IFN␥ signaling by SOCS proteins.
What the sources say
- Supportedcites [30] Brysha, 2001, J. Biol. Chem. source
The section ‘IFNγ-induced STAT Activation Is Prolonged in Mice’ reports that loss of SOCS-1 prolonged IFNγ-induced STAT1 phosphorylation without substantially changing its peak level. The Discussion likewise says SOCS-1 limits the duration, rather than the magnitude, of the response. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Tyrosine phosphorylation of STAT proteins is a valid measure of cytokine signaling and desensitization.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Interestingly, each of these stimuli activates the glycoprotein-130/STAT3 or the granulocytecolony stimulating factor-receptor/STAT3 signaling pathways, which are known to be inhibited by SOCS3 in vivo (24 -26, 29, 40, 41).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > FIGURE 8. Desensitization of IL-6 and IFN␥ signaling by SOCS proteins.
What the sources say
- Not checked — no full text of the sourcecites [24] Croker, 2003, Nat. Immunol. source
- Not checked — no full text of the sourcecites [25] Lang, 2003, Nat. Immunol. source
- Not checked — no full text of the sourcecites [26] Yasukawa, 2003, Nat. Immunol. source
- Not checked — no full text of the sourcecites [29] Croker, 2004, Immunity source
- Not checked — no full text of the sourcecites [40] Takahashi, 2003, EMBO J. source
- Supportedcites [41] Kimura, 2004, J. Biol. Chem. source
The paper’s results section reports stronger and more prolonged G-CSF-induced STAT3 activation in SOCS3-deficient neutrophils than in wild-type neutrophils, supporting SOCS3 inhibition of that pathway in vivo. The introduction also states that SOCS3 is essential for suppressing IL-6/gp130 signaling in macrophages. The supplied passages do not give page numbers. (LLM, conf=0.92)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“One likely candidate is interferon regulatory factor-1, because it is induced by STAT1 (32,42,43) and can associate with the Socs1 promoter to activate the transcription of Socs1 mRNA (18).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > FIGURE 8. Desensitization of IL-6 and IFN␥ signaling by SOCS proteins.
What the sources say
- Not checked — no full text of the sourcecites [32] Sims, 1993, Mol. Cell Biol. source
- Supportedcites [42] Haque, 1994, J. Biol. Chem. source
The Abstract reports IFN-α induction of IRF-1 and says the p91 subunit is required for formation of the promoter-binding factors. The Results (Fig. 5C; page unavailable) show that adding p91, but not p84, restores those factors in response to interferon. This supports the STAT1-dependent IRF-1 induction attributed to this source; the Socs1-promoter clause is cited separately to reference 18. (LLM, conf=0.85)
- Supportedcites [43] Pine, 1994, EMBO J. source
The Introduction identifies ISGF2 as IRF-1, and the section on p91 binding to the ISGF2 GAS says p91 is responsible for inducing its transcription. This supports the IRF-1 induction clause to which this source is cited; the separate Socs1-promoter clause is attributed to citation 18, not this paper. Page numbers are unavailable in our copy. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [18] Saito, 2000, J. Immunol. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“SOCS3 desensitized cells to IL-6 rapidly, whereas SOCS1mediated desensitization to IFN␥ occurred at later time points.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“phosphorylation declined to basal levels after 4 h in response to IFN␥ but after only 1 h in response to IL-6 (Fig. 1B).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Culture and Stimulation of C57BL/6, Socs3
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Surprisingly, heightened Socs1 mRNA expression but minimal STAT1 tyrosine phosphorylation was observed after prolonged stimulation with IFN␥”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“We also demonstrate that both SOCS1 and SOCS3 can desensitize primary bone marrowderived macrophages to IFN␥ and IL-6 signaling, respectively.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Both IFN␥ and IL-6 rapidly induced the activation of STATs, and in the absence of Socs1 and Socs3, respectively, continuous cytokine stimulation resulted in the sustained activation of STATs.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > FIGURE 8. Desensitization of IL-6 and IFN␥ signaling by SOCS proteins.
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, whereas the kinetics of induction of SOCS1 by IL-6 were similar to those induced by IFN␥, the magnitude was greatly reduced.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Differential Induction of STAT1 and STAT3 Tyrosine Phosphorylation by IFN␥ and IL-6 in the
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In the absence of Socs3, tyrosine phosphorylation of STAT3 in response to a 15-min pulse of IL-6 was extended until at least 90 min, with low level phosphorylation also apparent at later time points (Fig. 7A).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > SOCS3 Desensitizes Bone Marrow-derived Macrophages to
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: Tyrosine phosphorylation of STAT proteins is a valid measure of cytokine signaling and desensitization.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Three groups of genes with variable expression profiles were also identified by GeneCluster2 (data not shown).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > SOCS3 Is Responsible for Bi-phasic Tyrosine Phosphorylation of STAT3 and Expression of Genes in
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-6 induced both Socs1 and Socs3 mRNA to a similar extent, but more SOCS3 protein than SOCS1 protein”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Differential Induction of STAT1 and STAT3 Tyrosine Phosphorylation by IFN␥ and IL-6 in the
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This was followed by a rapid reduction of Socs3 mRNA expression, with minimal expression observed between 60 to 90 min, and subsequent re-establishment of expression by 180 min.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Differential Induction of STAT1 and STAT3 Tyrosine Phosphorylation by IFN␥ and IL-6 in the
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Socs1 mRNA and SOCS1 protein were induced to a greater extent by IFN␥ than by IL-6, whereas Socs3 mRNA and SOCS3 protein were induced more by IL-6 than by IFN␥.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > FIGURE 8. Desensitization of IL-6 and IFN␥ signaling by SOCS proteins.
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“expression of Socs1 mRNA was induced slowly, but remained at near-maximal levels from 60 min until at least 480 min.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > SOCS3 Is Responsible for Bi-phasic Tyrosine Phosphorylation of STAT3 and Expression of Genes in
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Several of the genes included in these groups were later determined by Q-PCR analysis to be regulated in the liver with a high degree of variability and not specifically in response to IFN␥ (data not shown).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > SOCS3 Is Responsible for Bi-phasic Tyrosine Phosphorylation of STAT3 and Expression of Genes in
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-6 induced the expression of SOCS3 protein very rapidly, with maximal levels detected 30 min to 1 h following injection, at a time that correlates with a decline in STAT1/STAT3 tyrosine phosphorylation (Fig. 1D; compare with Fig. 1, A and B)”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Differential Induction of STAT1 and STAT3 Tyrosine Phosphorylation by IFN␥ and IL-6 in the
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Yet despite the rapid phosphorylation of STAT1, the induction of Socs1 mRNA was slow.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > FIGURE 8. Desensitization of IL-6 and IFN␥ signaling by SOCS proteins.
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
- Rests on an assumption: Tyrosine phosphorylation of STAT proteins is a valid measure of cytokine signaling and desensitization.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The first phase occurred between 15 and 30 min, and the second from 120 min onward.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Differential Induction of STAT1 and STAT3 Tyrosine Phosphorylation by IFN␥ and IL-6 in the
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Again, IFN␥ induced Socs1 to greater levels than did IL-6, whereas IL-6 induced Socs3 to greater levels than did IFN␥.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Differential Induction of STAT1 and STAT3 Tyrosine Phosphorylation by IFN␥ and IL-6 in the
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“SOCS1 protein expression was maintained at a high level for at least 8 h, and declined to near basal levels by 16 h.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Differential Induction of STAT1 and STAT3 Tyrosine Phosphorylation by IFN␥ and IL-6 in the
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In C57BL/6 bone marrow-derived macrophages, regulation of continuous IL-6-signaling by SOCS3 was bi-phasic, with the first peak of IL-6 signaling appearing rapidly and transiently.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > FIGURE 8. Desensitization of IL-6 and IFN␥ signaling by SOCS proteins.
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IFN␥ induced the robust expression of SOCS1 protein, with levels reaching a maximum at 2-4 h after injection of IFN␥, at a time when STAT1 and STAT3 phosphorylation was waning (Fig. 1C; compare with Fig. 1, A and B).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Differential Induction of STAT1 and STAT3 Tyrosine Phosphorylation by IFN␥ and IL-6 in the
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Limited desensitization to IL-6 was, however, apparent for all re-stimulated Socs3-deficient cells, and was more pronounced at later time points”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > SOCS3 Desensitizes Bone Marrow-derived Macrophages to
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Tyrosine phosphorylation of STAT proteins is a valid measure of cytokine signaling and desensitization.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The decline in STAT3 phosphorylation from the initial peak at 15 min was rapid, and near-basal P-STAT3 levels were achieved by 60 min”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Differential Induction of STAT1 and STAT3 Tyrosine Phosphorylation by IFN␥ and IL-6 in the
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Surprisingly, prolonged IFN␥ signaling resulted in high levels of Socs1 mRNA expression, and low levels of STAT1 tyrosine phosphorylation.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > FIGURE 8. Desensitization of IL-6 and IFN␥ signaling by SOCS proteins.
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“After prolonged IL-6 signaling, medium levels of STAT3 activation, Socs3 mRNA expression, and presumably SOCS3 protein expression were observed.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > FIGURE 8. Desensitization of IL-6 and IFN␥ signaling by SOCS proteins.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Cells, of which more than 95% were macrophages (as determined by morphology), were then plated into 12-well tissue culturetreated plates (5 ϫ 10 5 cells/well) and incubated at 37 °C, 10% CO 2 .”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Culture and Stimulation of C57BL/6, Socs3
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“the generation of mice conditionally deficient for Socs3 revealed SOCS3 to be a potent physiological suppressor of IL-6 but not IFN␥ signaling (24 -26).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Abstract
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Importantly, changing the parameters specifying the number of clusters recognized by GeneCluster2 made little difference to the relationships observed between the responses to IFN␥ of livers from Ifn␥ Ϫ/Ϫ Socs1 Ϫ/Ϫ and Ifn␥ Ϫ/Ϫ mice.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > SOCS3 Is Responsible for Bi-phasic Tyrosine Phosphorylation of STAT3 and Expression of Genes in
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Physiologically, SOCS1 is the main inducible inhibitor of IFN␥ signaling and in neonatal mice prevents the establishment of a lethal inflammatory disease characterized by heightened levels of circulating IFN␥, fatty degeneration of the liver, and necrosis of the liver and other organs (22).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Abstract
What the sources say
- Not checked — no full text of the sourcecites [22] Alexander, 1999, Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Signaling by IL-6 and IFN␥ begins at the surface of the cell where the cytokines associate with their respective receptor complexes (1).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Abstract
What the sources say
- Not matchedcites [1] Nicola, 1994
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
In the paper
“These differences in the phosphorylation of STAT1 and STAT3 by IFN␥ and IL-6 are consistent with the role of STAT1 as an important mediator of the response to IFN␥ and the role of STAT3 as an important mediator of the response to IL-6 (21).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Culture and Stimulation of C57BL/6, Socs3
What the sources say
- Not checked — no full text of the sourcecites [21] Ihle, 2001, Curr. Opin. Cell Biol. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“it is uncertain whether the same is true for the genes grouped into cluster C, because sufficient discriminatory time points were not available.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > SOCS3 Is Responsible for Bi-phasic Tyrosine Phosphorylation of STAT3 and Expression of Genes in
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results seem to differ from the response to injection of IFN␥ that is observed in whole livers (Fig. 1, B and E), probably because the livers were taken from mice subjected to a single stimulation of IFN␥, whereas IFN␥ signaling in the bone marrowderived macrophages was continuous.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > SOCS3 Is Responsible for Bi-phasic Tyrosine Phosphorylation of STAT3 and Expression of Genes in
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results suggest that loss of Socs3 results in the prolonged expression of genes that are normally induced by IL-6 at early time points and in the heightened and uniform expression of genes that are normally induced by IL-6 with bi-phasic kinetics.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > SOCS3 Is Responsible for Bi-phasic Tyrosine Phosphorylation of STAT3 and Expression of Genes in
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“While only a single liver was used for each time point, differential expression was defined as relative induction or suppression of expression over at least two consecutive time points.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > FIGURE 9. A kinetic model of IFN␥ and IL-6 signal transduction dynamics for STAT activity, Socs mRNA expression, and SOCS protein expression.
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We demonstrated that both SOCS3 and SOCS1 desensitized bone marrow-derived macrophages to signaling by IL-6 and IFN␥, respectively, with the activity of SOCS1 occurring later than the activity of SOCS3.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > FIGURE 8. Desensitization of IL-6 and IFN␥ signaling by SOCS proteins.
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Tyrosine phosphorylation of STAT proteins is a valid measure of cytokine signaling and desensitization.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IFN␥ appears to induce SOCS1 protein expression relatively slowly, leading to slow inhibition and desensitization of signaling.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > FIGURE 8. Desensitization of IL-6 and IFN␥ signaling by SOCS proteins.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Tyrosine phosphorylation of STAT proteins is a valid measure of cytokine signaling and desensitization.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, IL-6 appears to induce SOCS3 protein expression rapidly, resulting in bi-phasic IL-6 signaling, and relatively rapid desensitization.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > FIGURE 8. Desensitization of IL-6 and IFN␥ signaling by SOCS proteins.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Tyrosine phosphorylation of STAT proteins is a valid measure of cytokine signaling and desensitization.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In conclusion, both SOCS1 and SOCS3 are able to desensitize cells to signaling by IFN␥ and IL-6, respectively.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > FIGURE 8. Desensitization of IL-6 and IFN␥ signaling by SOCS proteins.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Tyrosine phosphorylation of STAT proteins is a valid measure of cytokine signaling and desensitization.
The paper relies on this without support.
Tyrosine phosphorylation of STAT proteins is a valid measure of cytokine signaling and desensitization.
“Desensitization of Ifn␥ Ϫ/Ϫ macrophages (as measured by STAT1 tyrosine phosphorylation) following 15 min of IFN␥ signaling was observed after 120 min and until 360 min (Fig. 8B).”
The paper relies on this without support.
Little is known about the comparative induction of SOCS proteins by IFNγ and IL-6.
“however little is known of the comparative induction of SOCS proteins by IFN␥ and IL-6.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Differential Induction of STAT1 and STAT3 Tyrosine Phosphorylation by IFN␥ and IL-6 in the
“Expression of Socs3 mRNA was maximal at 30 min, 15 min after maximal STAT3 activation was observed (Fig. 3A).”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > FIGURE 9. A kinetic model of IFN␥ and IL-6 signal transduction dynamics for STAT activity, Socs mRNA expression, and SOCS protein expression.
“After ϳ1 h, the large concentration of phosphorylated STAT3 in the cell leads to a maximal induction of Socs3 mRNA and the accumulation of SOCS3 protein.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > Differential Induction of STAT1 and STAT3 Tyrosine Phosphorylation by IFN␥ and IL-6 in the
“The first phase occurred between 15 and 30 min, and the second from 120 min onward.”
§ The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling * > FIGURE 9. A kinetic model of IFN␥ and IL-6 signal transduction dynamics for STAT activity, Socs mRNA expression, and SOCS protein expression.
“After 3 h, the concentration of SOCS3 protein is sufficiently reduced to allow IL-6 signaling to resume.”
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Cited by
Sorted by citations
The molecular details of cytokine signaling via the JAK/STAT pathway
Morris, R., Kershaw, N. J., & Babon, J. J. (2018) · Protein Science · doi:10.1002/pro.3519 · Cited by 943
A Key Role of Leptin in the Control of Regulatory T Cell Proliferation
Rosa, V. D., Procaccini, C., Calı̀, G., Pirozzi, G., Fontana, S., Zappacosta, S., Cava, A. L., & Matarese, G. (2007) · Immunity · doi:10.1016/j.immuni.2007.01.011 · Cited by 646
SOCS3, a Major Regulator of Infection and Inflammation
Carow, B., & Rottenberg, M. E. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00058 · Cited by 555
“Interestingly, after the initial phosphorylation of STAT3 in response to IL-6 followed by a subsequent inhibition by SOCS3, a second wave of activation leads to the re-phosphorylation of STAT3 (101).”
BackgroundSTAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor
Wang, Y., van Boxel-Dezaire, A. H. H., Cheon, H., Yang, J., & Stark, G. R. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1315862110 · Cited by 327
“We confirm the observation of others (3, 26) that, after the initial phosphorylation of STAT3 in response to IL-6 and subsequent inhibition by SOCS3, a second wave of activation leads to the rephosphorylation of STAT3.”
ResultBabon, J. J., Kershaw, N. J., Murphy, J. M., Varghese, L. N., Laktyushin, A., Young, S. N., Lucet, I. S., Norton, R. S., & Nicola, N. A. (2012) · Immunity · doi:10.1016/j.immuni.2011.12.015 · Cited by 279
“, IL-6) will be effectively inhibited by SOCS3 (Wormald et al., 2006), whereas cytokines that signal through receptors that lack such a site (e.”
Self-citationLalancette-Hébert, M., Swarup, V., Beaulieu, J. M., Bohacek, I., Abdelhamid, E., Weng, Y. C., Sato, S., & Kriz, J. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.1498-12.2012 · Cited by 251
“This may lead to an overactivation of JAK/STAT pathway and upregulation of a feedback inhibitor SOCS3 (Wormald et al., 2006).”
BackgroundUps and downs: The STAT1:STAT3 seesaw of Interferon and gp130 receptor signalling
Regis, G., Pensa, S., Boselli, D., Novelli, F., & Poli, V. (2008) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2008.06.004 · Cited by 241
Inhibition of IL-6 family cytokines by SOCS3
Babon, J. J., Varghese, L. N., & Nicola, N. A. (2014) · Seminars in Immunology · doi:10.1016/j.smim.2013.12.004 · Cited by 224
Self-citationŠestan, M., Marinović, S., Kavazović, I., Cekinović, Đ., Wueest, S., Turk Wensveen, T., Brizić, I., Jonjić, S., Konrad, D., Wensveen, F. M., et al. (2018) · Immunity · doi:10.1016/j.immuni.2018.05.005 · Cited by 189
Reeh, H., Rudolph, N., Billing, U., Christen, H., Streif, S., Bullinger, E., Schliemann-Bullinger, M., Findeisen, R., Schaper, F., Huber, H. J., et al. (2019) · Cell Communication and Signaling · doi:10.1186/s12964-019-0356-0 · Cited by 180
Suppressors of Cytokine Signaling Abrogate Diabetic Nephropathy
Ortiz-Muñoz, G., López-Parra, V., López‐Franco, Ó., Fernández‐Vizarra, P., Mallavia, B., Flores, C., Sanz, A. B., Blanco, J., Mezzano, S. A., Ortíz, A., et al. (2010) · Journal of the American Society of Nephrology · doi:10.1681/asn.2009060625 · Cited by 180
Liu, Y., Stewart, K. N., Bishop, E., Marek, C. J., Kluth, D., Rees, A. J., & Wilson, H. M. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.9.6270 · Cited by 168
“This was surprising because IFN- is a prominent activating cytokine in glomeruli in acute nephritis, and in vitro studies have documented that macrophages activated by IFN- have increased expression of both SOCS1 and SOCS3 (16, 26).”
BackgroundResultInfluentialTranslational and clinical advances in JAK-STAT biology: The present and future of jakinibs
Gadina, M., Johnson, C., Schwartz, D. M., Bonelli, M. M., Hasni, S., Kanno, Y., Changelian, P. S., Laurence, A. D. J., & O’Shea, J. J. (2018) · Journal of Leukocyte Biology · doi:10.1002/jlb.5ri0218-084r · Cited by 162
Maher, S., Sheikh, F. G., Scarzello, A. J., Romero-Weaver, A. L., Baker, D., Donnelly, R., & Gamero, A. (2008) · Cancer Biology & Therapy · doi:10.4161/cbt.7.7.6192 · Cited by 95
Macrophage Proinflammatory Activation and Deactivation
Valledor, A. F., Comalada, M., Santamaria‐Babí, L. F., Lloberas, J., & Celada, A. (2010) · Advances in immunology · doi:10.1016/b978-0-12-380995-7.00001-x · Cited by 160
The biology and mechanism of action of suppressor of cytokine signaling 3
Babon, J. J., & Nicola, N. A. (2012) · Growth Factors · doi:10.3109/08977194.2012.687375 · Cited by 129
“For example, both interferon g and IL-6 activate JAK1 and JAK2, STAT1 and STAT3, and SOCS1 and SOCS3 albeit with different kinetics and different strengths (Wormald et al. 2006).”
BackgroundSelf-citationSuppressors of Cytokine Signaling Modulate JAK/STAT-Mediated Cell Responses During Atherosclerosis
Ortiz-Muñoz, G., Martı́n-Ventura, J. L., Hernández-Vargas, P., Mallavia, B., López-Parra, V., López‐Franco, Ó., Muñoz‐García, B., Fernández‐Vizarra, P., Ortega, L. M., Egido, J., et al. (2009) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.108.173781 · Cited by 124
The Helix-Loop-Helix Protein ID2 Governs NK Cell Fate by Tuning Their Sensitivity to Interleukin-15
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Self-citationBehar, M., Hao, N., Dohlman, H. G., & Elston, T. C. (2007) · Biophysical Journal · doi:10.1529/biophysj.107.107516 · Cited by 110
“1⁄2P 1 1⁄2P 1⁄4 1 1⁄2K 1 1⁄2K 1⁄4 1: (4)”
BackgroundWang, W., Edington, H. D. J., Rao, U. N. M., Jukic, D. M., Land, S. R., Ferrone, S., & Kirkwood, J. M. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-1387 · Cited by 109
Division of labor by dual feedback regulators controls JAK2/STAT5 signaling over broad ligand range
Bachmann, J., Raue, A., Schilling, M., Böhm, M. E., Kreutz, C., Kaschek, D., Busch, H. S., Gretz, N., Lehmann, W. D., Timmer, J., et al. (2011) · Molecular Systems Biology · doi:10.1038/msb.2011.50 · Cited by 107
“A prime example for the evidence that two SOCS proteins uniquely attenuate STAT dynamics is the study of Wormald et al (2006) showing that SOCS1 and SOCS3 regulate STAT1 and STAT3 phosphorylation dynamics with different kinetics.”
The SPRY domain–containing SOCS box protein SPSB2 targets iNOS for proteasomal degradation
Kuang, Z., Lewis, R. S., Curtis, J., Zhan, Y., Saunders, B. M., Babon, J. J., Kolesnik, T. B., Low, A., Masters, S. L., Willson, T. A., et al. (2010) · The Journal of Cell Biology · doi:10.1083/jcb.200912087 · Cited by 104
“…by culture of whole bone marrow in DME supplemented with 100 U/ml penicillin, 0.1 mg/ml streptomycin, 10% FBS (Sigma-Aldrich), and 20% L-cell–conditioned medium as a source of macrophage colony-stimulating factor (Wormald et al., 2006) and maintained at 37°C in a humidified atmosphere with 10% CO2.”
InfluentialYeddula, N., & Balaji, K. N. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m709960200 · Cited by 93
de Souza, J. A. C., Nogueira, A. V. B., de Souza, P. P. C., Kim, Y. J., Lobo, C. S., de Oliveira, G. J. P. L., Cirelli, J. A., Garlet, G. P., & Rossa, C. (2013) · Mediators of Inflammation · doi:10.1155/2013/650812 · Cited by 93
“The “specificity” of SOCS3 attenuating STAT3 has been shown indirectly by studies reporting higher and prolonged STAT3 activation in vivo conditional knockout animals with deletion of SOCS3 in macrophages [23], as well as in murine macrophages in vitro upon IL-6 stimulation [24].”
Essential biphasic role for JAK3 catalytic activity in IL-2 receptor signaling
Smith, G. A., Uchida, K., Weiss, A., & Taunton, J. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2056 · Cited by 87
Linossi, E. M., & Nicholson, S. E. (2015) · Immunological Reviews · doi:10.1111/imr.12305 · Cited by 86
“For example, injection of mice with IFN-c leads to increased SOCS1 mRNA and protein in the spleen within 60 minutes (22).”
BackgroundMcKay, B. R., Ogborn, D. I., Baker, J. M., Toth, K., Tarnopolsky, M. A., & Parise, G. (2013) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00305.2012 · Cited by 87
“This may be partially explained by the elevated basal SOCS3 in the muscle, which may have desensitized the SCs to IL-6 (20, 62).”
BackgroundWoodward, E., Prêle, C. M., Nicholson, S. E., Kolesnik, T. B., & Hart, P. H. (2010) · Immunology · doi:10.1111/j.1365-2567.2010.03281.x · Cited by 82
Kurdi, M., & Booz, G. W. (2007) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0b013e318068dd49 · Cited by 80
“In this regard, it is important to point out that contrary to earlier conclusions based on overexpression experiments, recent knockout studies indicate that while IFNg induces both SOCS3 and SOCS1; the latter is the important physiological regulator of its signaling (Table 4).(143) Evidence was recently reported as we…”
ResultKedzierski, Ł., Tate, M. D., Hsu, A., Kolesnik, T. B., Linossi, E. M., Dagley, L. F., Dong, Z., Freeman, S., Infusini, G., Starkey, M. R., et al. (2017) · eLife · doi:10.7554/elife.20444 · Cited by 72
“Another example is the modest difference seen in IFN signaling in SOCS1-deficient cells (Brysha et al., 2001; Wormald et al., 2006).”
BackgroundSelf-citationZadjali, F., Santana‐Farré, R., Vesterlund, M., Carow, B., de Mirecki-Garrido, M., Hernández, I., Flodström‐Tullberg, M., Parini, P., Rottenberg, M. E., Norstedt, G., et al. (2012) · The FASEB Journal · doi:10.1096/fj.12-205583 · Cited by 74
“SOCS3 also has activity toward the leptin receptor (5, 6).”
BackgroundDose-to-Duration Encoding and Signaling beyond Saturation in Intracellular Signaling Networks
Behar, M., Hao, N., Dohlman, H. G., et al. (2008) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1000197 · Cited by 67
“This type of architecture plays a role in the regulation of ERK signaling by the enzymatic activation of members of the MAPK phosphatase group (MKP’s) [15–17], and in the regulation of cytokine signaling by the induction of suppressor of cytokine signaling (SOCS) proteins [18].”
BackgroundLiu, Z.-K., Li, C., Zhang, R., et al. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01377-9 · Cited by 64
“demonstrated that SOCS3 was required for bi-phasic STAT3 tyrosine phosphorylation with IL-6 stimulation [36].”
BackgroundInduction of Suppressors of Cytokine Signaling by the Trichothecene Deoxynivalenol in the Mouse
Amuzie, C. J., Shinozuka, J., & Pestka, J. J. (2009) · Toxicological Sciences · doi:10.1093/toxsci/kfp150 · Cited by 59
“It was surprising that SOCS1 was nondetectable in the liver of mice, in contrast to another study (Wormald et al., 2006).”
BackgroundResultZhao, C., Mirando, A. C., Sové, R. J., Medeiros, T. X., Annex, B. H., & Popel, A. S. (2019) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1007468 · Cited by 62
“In response to different doses of IFN-γ treatment, the model simulations are compared with corresponding literature time-course data including (A) degradation of receptor-bound IFN-γ [59], (B) phosphorylation of receptor-associated JAK [15], (C) phosphorylation of STAT1 [60], (D) expression of IRF-1 [61], (E) expressi…”
Masood, K. I., Rottenberg, M. E., Salahuddin, N., Irfan, M., Rao, N. A., Carow, B., Islam, M., Hussain, R., & Hasan, Z. (2013) · BMC Infectious Diseases · doi:10.1186/1471-2334-13-13 · Cited by 58
“Expression levels of the Suppressor of Cytokine Signaling (SOCS) molecules are found to be raised in patients with active TB [17] and are thought to play a role in regulation of cytokine secretion and responses [18].”
TLR Regulation of SPSB1 Controls Inducible Nitric Oxide Synthase Induction
Lewis, R. S., Kolesnik, T. B., Kuang, Z., D’Cruz, A. A., Blewitt, M. E., Masters, S. L., Low, A., Willson, T. A., Norton, R. S., & Nicholson, S. E. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1002993 · Cited by 58
“E-mail address: snicholson@wehi.edu.au Abbreviations used in this article: BMDM, bone marrow-derived macrophage; iNOS, inducible NO synthase; M-CSF, macrophage colony stimulating factor; poly-IC, polyinosinic-polycytidylic acid; qPCR, quantitative PCR; shRNA, short hairpin RNA; TRIF, TIR domain-containing adapter indu…”
MethodInfluentialWalker, E. C., Johnson, R. W., Hu, Y., Brennan, H. J., Poulton, I. J., Zhang, J., Jenkins, B. J., Smyth, G. K., Nicola, N. A., & Sims, N. A. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.748483 · Cited by 57
Self-citationMcCormick, S. M., Gowda, N. M., Fang, J., & Heller, N. M. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.746164 · Cited by 56
“In mouse models of asthma, decreases in SOCS1 correlated with an increase in SOCS3, suggesting reciprocal regulation of SOCS1 and SOCS3 in allergic disease (89).”
BackgroundThe Multifaceted Role of STAT3 in NK-Cell Tumor Surveillance
Witalisz‐Siepracka, A., Klein, K., Moser, B., & Stoiber, D. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.947568 · Cited by 57
“The effects of SOCS3 on STAT3 activation might depend on the upstream stimuli, which are likely to be differently susceptible to SOCS3-mediated inhibition (109, 110).”
BackgroundSOCS1 controls liver regeneration by regulating HGF signaling in hepatocytes
Gui, Y., Yeganeh, M., Ramanathan, S., LeBlanc, C., Pomerleau, V., Ferbeyre, G., Saucier, C., & Ilangumaran, S. (2011) · Journal of Hepatology · doi:10.1016/j.jhep.2011.03.027 · Cited by 57
“Transcription of Socs1 and Socs3 genes in the liver is induced by PH and following systemic administration of IL-6 [20,31,32].”
BackgroundHalenius, A., Hauka, S., Dölken, L., et al. (2011) · Journal of Virology · doi:10.1128/jvi.01923-10 · Cited by 49
“Successful actD blocking of the RNA polymerase was confirmed by the disappearance of SOCS3 mRNA, which has been shown to have a half-life of only 30 min (59).”
BackgroundThe RON Receptor Tyrosine Kinase Regulates IFN-γ Production and Responses in Innate Immunity
Wilson, C. B., Ray, M., Lutz, M., Sharda, D. R., Xu, J., & Hankey, P. A. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.4.2303 · Cited by 47
“IL-6 and IL-10 induce SOCS-3 via a STAT3-dependent mechanism (48).”
BackgroundRole of cytokines in head and neck squamous cell carcinoma
Pries, R., Nitsch, S., & Wollenberg, B. (2006) · Expert Review of Anticancer Therapy · doi:10.1586/14737140.6.9.1195 · Cited by 47
Berard, J. L., Kerr, B. J., Johnson, H. M., & David, S. (2010) · Glia · doi:10.1002/glia.21051 · Cited by 46
“, 2002) and diminishes macrophage responsiveness to proinflammatory cytokines (Wormald et al., 2006).”
BackgroundYang, H., Xu, H., Wang, Z., Li, X., Wang, P., Cao, X., Xu, Z., Lv, D., Rong, Y., Chen, M., et al. (2023) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2023.110573 · Cited by 45
Suppressor of cytokine signalling 1 (SOCS1) is a physiological regulator of the asthma response
Lee, C., Kolesnik, T. B., Caminschi, I., Chakravorty, A., Carter, W., Alexander, W. S., Jones, J. E. C., Anderson, G. P., & Nicholson, S. E. (2009) · Clinical & Experimental Allergy · doi:10.1111/j.1365-2222.2009.03217.x · Cited by 44
Self-citationJin, H., Xiang, L.-X., & Shao, J.-Z. (2007) · Immunogenetics · doi:10.1007/s00251-007-0232-8 · Cited by 45
“The SOCS protein family consists of eight known members (SOCS-1 to SOCS-7 and cytokineinduced Src-homology [SH] 2 [CISH]), all sharing a central SH2 domain (binds proteins at the sites of phosphorylated tyrosine residues), a conserved SOCS box (a 40 amino acid domain in the carboxyl terminal domain), and a variable am…”
BackgroundSystems biology of IL-6, IL-12 family cytokines
Dittrich, A., Hessenkemper, W., & Schaper, F. (2015) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2015.07.002 · Cited by 42
“analyzed in detail in hepatoma cells [48] and bone marrow derived macrophages [49].”
BackgroundGrowth Hormone Resistance—Special Focus on Inflammatory Bowel Disease
Soendergaard, C., Young, J. A., & Kopchick, J. J. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18051019 · Cited by 44
Transcription Protein STAT1: Biology and Relation to Cancer
Adámková, L., Součková, K., & Kovařík, J. (2007) · Folia Biologica · doi:10.14712/fb2007053010001 · Cited by 41
Cho, D.-C., Brennan, H. J., Johnson, R. W., Poulton, I. J., Gooi, J. H., Tonkin, B. A., McGregor, N. E., Walker, E. C., Handelsman, D. J., Martin, T. J., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00920-x · Cited by 40
GHR signalling: Receptor activation and degradation mechanisms
Chhabra, Y., Lee, C. M. M., Mueller, A., & Brooks, A. J. (2020) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2020.111075 · Cited by 42
Chang, C., Lin, C., Lee, C., Chuang, H., Shih, F.-C., Wan, S.-W., Tai, C., & Chen, C. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.114356 · Cited by 40
Hepatocyte growth control by SOCS1 and SOCS3
Khan, M. G. M., Ghosh, A., Variya, B. C., Santharam, M. A., Kandhi, R., Ramanathan, S., & Ilangumaran, S. (2019) · Cytokine · doi:10.1016/j.cyto.2019.154733 · Cited by 38
PARP-14 Binds Specific DNA Sequences to Promote Th2 Cell Gene Expression
Riley, J. P., Kulkarni, A., Mehrotra, P., Koh, B., Perumal, N. B., Kaplan, M. H., & Goenka, S. (2013) · PLoS ONE · doi:10.1371/journal.pone.0083127 · Cited by 40
“We further evaluated the expression of Socs1, Socs2 and Socs3, known regulators of the STAT transcription factors [37,38].”
MethodComplex systems biology approach to understanding coordination of JAK-STAT signaling
Soebiyanto, R. P., Sreenath, S. N., Qu, C., Loparo, K. A., & Bunting, K. D. (2007) · Biosystems · doi:10.1016/j.biosystems.2007.05.005 · Cited by 38
SOCS1: Regulator of T Cells in Autoimmunity and Cancer
Ilangumaran, S., Bobbala, D., & Ramanathan, S. (2017) · Current topics in microbiology and immunology · doi:10.1007/82_2017_63 · Cited by 37
Adiponectin induces interleukin‐6 production and activates STAT3 in adult mouse cardiac fibroblasts
Liao, W., Yu, C., Wen, J., Jia, W. W.-G., Geng, L., Ke, Y.-N., Zhao, S., & Campell, W. B. (2008) · Biology of the Cell · doi:10.1042/bc20080117 · Cited by 37
“SOCS-3 is an early response gene, potently induced by various factors, such as leukemia inhibitory factor, IL-1β, IL-6, insulin growth factor-1, erythropoietin and leptin (Patrick et al., 2004; Laubner et al., 2005; Yadav et al., 2005; Wormald et al., 2006; Isomoto et al., 2007; Boyle and Robb, 2008).”
BackgroundInfluentialHIV interferes with SOCS‐1 and ‐3 expression levels driving immune activation
Miller, R. C., Schlaepfer, E., Baenziger, S., Crameri, R., Zeller, S., Byland, R., Audigé, A., Nadal, D., & Speck, R. F. (2011) · European Journal of Immunology · doi:10.1002/eji.201041198 · Cited by 37
Xiao, Z., Liu, H., Fu, J.-P., Hu, W., Wang, Y., & Guo, Q. (2009) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2009.11.012 · Cited by 36
Deepe, G. S., & Buesing, W. R. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1102175 · Cited by 36
“Moreover, SOCS3 depresses IFN-g signaling, thus blunting another antifungal host-defense mechanism (60).”
BackgroundRapid Inflammation in Mice Lacking Both SOCS1 and SOCS3 in Hematopoietic Cells
Ushiki, T., Huntington, N. D., Glaser, S. P., Kiu, H., Georgiou, A., Zhang, J., Metcalf, D., Nicola, N. A., Roberts, A. W., & Alexander, W. S. (2016) · PLoS ONE · doi:10.1371/journal.pone.0162111 · Cited by 37
Self-citationA Potent Cyclic Peptide Targeting SPSB2 Protein as a Potential Anti-infective Agent
Yap, B. K., Leung, E. W. W., Yagi, H., Galea, C. A., Chhabra, S., Chalmers, D. K., Nicholson, S. E., Thompson, P. E., & Norton, R. S. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm500596j · Cited by 35
Interaction and Functional Interference of Glucocorticoid Receptor and SOCS1
Haffner, M. C., Jurgeit, A., Berlato, C., Geley, S., Parajuli, N., Yoshimura, A., & Doppler, W. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m801041200 · Cited by 37
Nerstedt, A., Cansby, E., Amrutkar, M., Smith, U., & Mahlapuu, M. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.05.013 · Cited by 36
“As previously reported (Wormald et al., 2006), a significantly increased Tyr705 phosphorylation of STAT3 was observed in liver 15 min after IL-6 administration, which was further increased at 45 min post-injection (p 0.01, Fig.”
BackgroundInfluentialRateitschak, K., Karger, A., Fitzner, B., Lange, F., Olaf Wolkenhauer, A., & Jaster, R. (2009) · Cellular Signalling · doi:10.1016/j.cellsig.2009.09.019 · Cited by 34
Li, J., Zhang, Y., Zhang, Y., Liu, Y., Xiang, Z., Qu, F., & Yu, Z. (2015) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2015.03.022 · Cited by 32
Iwahara, N., Hisahara, S., Kawamata, J., Matsumura, A., Yokokawa, K., Saito, T., Fujikura, M., Manabe, T., Suzuki, H., Matsushita, T., et al. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160887 · Cited by 34
“SOCS3 is known to be upregulated by IL10, interferon (cid:5) (IFN (cid:5) ), or IL6 in macrophage through JAK2/STAT3 activation [22].”
Zhang, X., Alnaeeli, M., Singh, B., & Teng, Y.-T. A. (2009) · Infection and Immunity · doi:10.1128/iai.01070-08 · Cited by 31
“Of particular interest to us is SOCS3, as it has been previously shown to be involved during inflammation-induced osteoclastogenesis and its activity is closely associated with key osteotropic cytokines, such as interleukin-1 (IL-1), TNF-, transforming growth factor , IL-6, IL-17, etc. (8, 10, 11, 35, 43, 60 ).”
BackgroundInfluentialA Prototype QSP Model of the Immune Response to SARS‐CoV‐2 for Community Development
Dai, W., Rao, R. P., Sher, A., Tania, N., Musante, C. J., & Allen, R. (2020) · CPT Pharmacometrics & Systems Pharmacology · doi:10.1002/psp4.12574 · Cited by 30
“Additionally, the ability of IFN-γ and IL-6 to negatively regulate each other’s activity is also incorporated.(28)”
BackgroundMechanism of attenuation of leptin signaling under chronic ligand stimulation
Knobelspies, H., Zeidler, J., Hekerman, P., Bamberg‐Lemper, S., & Becker, W. B. (2010) · BMC Biochemistry · doi:10.1186/1471-2091-11-2 · Cited by 31
“Hence, differences in requirement of recruitment sites, in addition to differences in the induction by various cytokines and different kinetics of induction [60], critically determine the modulatory effects of SOCS1 and SOCS3 on cytokine receptor signaling.”
Altered levels of STAT1 and STAT3 influence the neuronal response to interferon gamma
Rose, R. W., Vorobyeva, A. G., Skipworth, J. D., Nicolas, É., & Rall, G. F. (2007) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2007.10.007 · Cited by 28
Wormald, S., & Hilton, D. J. (2007) · Current Opinion in Hematology · doi:10.1097/00062752-200701000-00004 · Cited by 29
Self-citationLange, F., Rateitschak, K., Fitzner, B., Pöhland, R., Olaf Wolkenhauer, A., & Jaster, R. (2011) · Molecular Cancer · doi:10.1186/1476-4598-10-13 · Cited by 26
“The initial value of STAT1 results from the optimization of the initial values of STAT1Dc, STAT1Uc and STAT1Un.”
BackgroundInfluentialHarjani, J. R., Yap, B. K., Leung, E. W. W., Lucke, A. J., Nicholson, S. E., Scanlon, M. J., Chalmers, D. K., Thompson, P. E., Norton, R. S., & Baell, J. B. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00386 · Cited by 25
Intracellular Delivery of a Cell-Penetrating SOCS1 that Targets IFN-γ Signaling
DiGiandomenico, A., Wylezinski, L. S., & Hawiger, J. (2009) · Science Signaling · doi:10.1126/scisignal.1162191 · Cited by 24
MicroRNA Regulation of T-Cell Exhaustion in Cutaneous T Cell Lymphoma
Han, Z., Estephan, R. J., Wu, X., Su, C., Yuan, Y., Qin, H., Kil, S. H., Morales, C. J., Schmolze, D. B., Sanchez, J. F., et al. (2021) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2021.08.447 · Cited by 23
STAT3 modulates β-cell cycling in injured mouse pancreas and protects against DNA damage
Groef, S. D., Renmans, D., Cai, Y., Leuckx, G., Roels, S., Staels, W., Gradwohl, G., Baeyens, L., Heremans, Y., Martens, G. A., et al. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.171 · Cited by 22
Gfap and Osmr regulation by BRG1 and STAT3 via interchromosomal gene clustering in astrocytes
Ito, K., Noguchi, A., Uosaki, Y., Taga, T., Arakawa, H., & Takizawa, T. (2017) · Molecular Biology of the Cell · doi:10.1091/mbc.e17-05-0271 · Cited by 23
“The initial phosphorylation is transient although in some conditions it is biphasic, which leads to a second wave of gene expression (Croker et al., 2003; Wormald et al., 2006; Wang et al., 2013).”
BackgroundSOCS3 expression induced by PIM2 requires PKC and PI3K signaling
Yeddula, N., Bansal, K., Sinha, A. Y., Kapoor, N., Puzo, G., Gilleron, M., & Balaji, K. N. (2009) · Molecular Immunology · doi:10.1016/j.molimm.2009.06.019 · Cited by 20
Redox‐stable cyclic peptide inhibitors of the SPSB2–iNOS interaction
Yap, B. K., Harjani, J. R., Leung, E. W. W., Nicholson, S. E., Scanlon, M. J., Chalmers, D. K., Thompson, P. E., Baell, J. B., & Norton, R. S. (2016) · FEBS Letters · doi:10.1002/1873-3468.12115 · Cited by 19
Proximal genomic localization of STAT1 binding and regulated transcriptional activity
Wormald, S., Hilton, D. J., Smyth, G. K., & Speed, T. P. (2006) · BMC Genomics · doi:10.1186/1471-2164-7-254 · Cited by 19
Self-citationPodolsky, M. A., Solomos, A. C., Durso, L. C., Evans, S. M., Rall, G. F., & Rose, R. W. (2012) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2012.06.006 · Cited by 18
“For example, the expression of suppressor of cytokine signaling (SOCS)-1 is induced in response to IFN-γ; it binds to IFN-γ receptor-associated JAKs and thereby prevents continued phosphorylation of the IFNGR1 subunits (Endo et al., 1997; Yasukawa et al., 1999; Giordanetto and Kroemer, 2003; Wormald et al., 2006), eff…”
BackgroundInfluentialO’Sullivan, L. A., Noor, S. M., Trengove, M. C., Lewis, R. S., Liongue, C., Sprigg, N. S., Nicholson, S. E., & Ward, A. C. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1000343 · Cited by 16
“Indeed, macrophage sensitivity to IFN-g is significantly increased in Socs1-deficient mice (80).”
BackgroundDJC Suppresses Advanced Glycation End Products‐Induced JAK‐STAT Signaling and ROS in Mesangial Cells
Sun, M., Li, Y., Bu, W., Zhao, J., Zhu, J., Gu, L., Zhang, P., & Fang, Z. (2017) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2017/2942830 · Cited by 18
Aboulhoda, B. E. (2017) · Annals of Anatomy - Anatomischer Anzeiger · doi:10.1016/j.aanat.2017.07.003 · Cited by 15
Zhang, Z., Zeng, B., Zhang, Z., Jiao, G., Li, H., Jing, Z., Ouyang, J., Yuan, X., Chai, L., Che, Y., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-2744 · Cited by 14
Mechanism of crosstalk inhibition of IL-6 signaling in response to LPS and TNFα
Kiu, H., Hilton, D. J., Nicola, N. A., Ernst, M., Márquez, R., Alexander, W. S., Roberts, A. W., & McManus, E. J. (2007) · Growth Factors · doi:10.1080/08977190701830151 · Cited by 14
“By directly binding to phospho-Tyr757 of the IL-6 receptor subunit gp130, SOCS3 acts as a negative regulator of IL-6 signaling (Croker et al. 2003; Lang et al. 2003; Yasukawa et al. 2003; Wormald et al. 2006), and both LPS and TNFa induce SOCS3 (Bode et al.”
BackgroundInfluentialSelf-citationRelationship between circadian genes and memory impairment caused by sleep deprivation
Ke, P., Zheng, C., Liu, F., Wu, L., Tang, Y., Wu, Y., Lv, D., Chen, H., Qian, L., Wu, X., et al. (2022) · PeerJ · doi:10.7717/peerj.13165 · Cited by 15
“…reliability of the results, multiple datasets, including GSE9442 (brain), GSE98582 (human blood) ( Uyhelji et al., 2018 ), GSE42323 (mice heart) ( Wormald et al., 2006 ), GSE92913 (mice liver) ( Fan et al., 2021 ), and GSE42324 (mice lung) ( Anafi et al., 2013 ), were used to verify the…”
Simon, R., Heithoff, D. M., Mahan, M. J., et al. (2007) · Infection and Immunity · doi:10.1128/iai.01021-07 · Cited by 13
“the following proteins (35, 51): iNOS (Fig.”
BackgroundJiang, K., Krous, L. C., Knowlton, N. S., Chen, Y., Frank, M. B., Cadwell, C., Centola, M. B., & Jarvis, J. N. (2009) · Placenta · doi:10.1016/j.placenta.2009.06.006 · Cited by 11
“We have discussed the limits of over-interpreting the network structures that emerge from Ingenuity Pathways Analysis in another paper [30], but this finding is compatible with what we are now learning about genome-wide control of gene expression in model organisms [31–33].”
ResultLeung, E. W. W., Mulcair, M. D., Yap, B. K., Nicholson, S. E., Scanlon, M. J., & Norton, R. S. (2016) · Australian Journal of Chemistry · doi:10.1071/ch16510 · Cited by 11
Clowers, M. J., & Moghaddam, S. J. (2022) · Cancers · doi:10.3390/cancers14071785 · Cited by 9
Mechanism of herpesvirus protein kinase UL13 in immune escape and viral replication
Zhou, L., Cheng, A., Wang, M., Wu, Y., Yang, Q., Tian, B., Ou, X., Sun, D., Zhang, S., Mao, S., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1088690 · Cited by 9
A unified approach to dissecting biphasic responses in cell signaling
Ramesh, V., & Krishnan, J. (2023) · eLife · doi:10.7554/elife.86520 · Cited by 8
“Tyrosine phosphorylation of STAT3 protein, in the presence of SOCS3, is biphasic in response to continuous IL-6 signaling, and monophasic without SOCS3 ( Wormald et al., 2006 ).”
BackgroundRegulation of STAT3 signaling in IFNγ and IL10 pathways and in their cross-talk
Sarma, U., Maiti, M., Nair, A., et al. (2021) · Cytokine · doi:10.1016/j.cyto.2021.155665 · Cited by 8
TGF-β and IL-6 family signalling crosstalk: an integrated model
Khatibi, S., Babon, J. J., Wagner, J., Manton, J. H., Tan, C. W., Zhu, H., Wormald, S., & Burgess, A. W. (2017) · Growth Factors · doi:10.1080/08977194.2017.1363746 · Cited by 7
“Experimental data: Experimental data and kinetic rates for IL-6 signalling in the liver were derived from Wormald et al. published in 2006 (Wormald et al., 2006).”
BackgroundMethodResultInfluentialSelf-citationKolseth, I. B. M., Førland, D. T., Risøe, P. K., Kjeldsen, S. F., Ågren, J., Reseland, J. E., Lyngstadaas, S. P., Johnson, E., & Dahle, M. K. (2012) · Scandinavian Journal of Clinical and Laboratory Investigation · doi:10.3109/00365513.2012.721520 · Cited by 6
Petrova, G., Petrov, S., & Bancheva, S. T. (2016) · INFM-OAR (INFN Catania) · doi:10.5281/zenodo.200406 · Cited by 6
Metadata
- Authors
- Wormald, S., Zhang, J.-G., Krebs, D. L., Mielke, L. A., Silver, J., Alexander, W. S., Speed, T. P., Nicola, N. A., & Hilton, D. J.
- Affiliations
- Walter and Eliza Hall Institute of Medical Research (AU)
- Corresponding author
- Wormald, Samuel
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-04
- Volume
- 281
- Issue
- 16
- Pages
- 11135-11143
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2019667607
- Cited by
- 123
- References
- 44
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 2 · 2022: 9 · 2021: 5 · 2020: 3 · 2019: 3 · 2018: 4 · 2017: 8 · 2016: 13 · 2015: 4 · 2014: 3 · 2013: 6 · 2012: 8
- FWCI
- 5.43
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (CA22556)
- National Cancer Institute (CA22556)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- SOCS1, SOCS3, cytokine signaling, negative feedback, STAT1 tyrosine phosphorylation, STAT3 tyrosine phosphorylation, interferon-gamma signaling, IL-6 signaling, signal transduction kinetics, bone marrow-derived macrophages, liver, gene expression kinetics
- MeSH terms
- Suppressor of Cytokine Signaling 1 Protein, Suppressor of Cytokine Signaling 3 Protein, Animals, Bone Marrow Cells, Carrier Proteins, Interferon-gamma, Kinetics, Macrophages, Mice, Inbred C57BL, Mice, Transgenic, Phosphorylation, Repressor Proteins, RNA, RNA, Messenger, Time Factors, Tyrosine, Blotting, Western, Signal Transduction, Interleukin-6, Cluster Analysis, Polymerase Chain Reaction, Cytokines, DNA, Complementary, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Immunoprecipitation, Suppressor of Cytokine Signaling Proteins, Mice
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