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
22 of 57 cited sources checked · 14 supported · 0 flagged · 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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe 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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesEvery 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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- 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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesEvery 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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- 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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesEvery 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)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- 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)
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- 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)
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- 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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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)
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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, 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Strength:plain· not yet calibratedSingle caseTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
SOCS3 mRNA peak is placed at two different times
MinorThe results state that Socs3 mRNA expression was maximal at 30 min, whereas the kinetic model places maximal induction after approximately 1 h.
“Expression of Socs3 mRNA was maximal at 30 min, 15 min after maximal STAT3 activation was observed (Fig. 3A).”
“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.”
Second phase of IL-6 signaling begins at conflicting times
MinorThe results place the second phase of STAT3 phosphorylation at 120 min onward, but the kinetic model says IL-6 signaling resumes after 3 h.
“The first phase occurred between 15 and 30 min, and the second from 120 min onward.”
“After 3 h, the concentration of SOCS3 protein is sufficiently reduced to allow IL-6 signaling to resume.”
Citations
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Flagged first, then by citations
Research works printed but not linked: 2
- Sims, 1993, Mol. Cell Biol., 13, 690
- Nakajima, 1991, Mol. Cell Biol., 11, 1409
Cited by
Sorted by citations
The molecular details of cytokine signaling via the JAK/STAT pathway
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“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
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“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-citation
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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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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