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Principles of interleukin (IL)-6-type cytokine signalling and its regulation
Open accessAbstract
The IL (interleukin)-6-type cytokines IL-6, IL-11, LIF (leukaemia inhibitory factor), OSM (oncostatin M), ciliary neurotrophic factor, cardiotrophin-1 and cardiotrophin-like cytokine are an important family of mediators involved in the regulation of the acute-phase response to injury and infection. Besides their functions in inflammation and the immune response, these cytokines play also a crucial role in haematopoiesis, liver and neuronal regeneration, embryonal development and fertility. Dysregulation of IL-6-type cytokine signalling contributes to the onset and maintenance of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis and various types of cancer (e.g. multiple myeloma and prostate cancer). IL-6-type cytokines exert their action via the signal transducers gp (glycoprotein) 130, LIF receptor and OSM receptor leading to the activation of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and MAPK (mitogen-activated protein kinase) cascades. This review focuses on recent progress in the understanding of the molecular mechanisms of IL-6-type cytokine signal transduction. Emphasis is put on the termination and modulation of the JAK/STAT signalling pathway mediated by tyrosine phosphatases, the SOCS (suppressor of cytokine signalling) feedback inhibitors and PIAS (protein inhibitor of activated STAT) proteins. Also the cross-talk between the JAK/STAT pathway with other signalling cascades is discussed.
Overview
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Written from the paper’s full text.
TL;DR
This review summarizes IL-6-type cytokine signalling through gp130, LIFR and OSMR, covering JAK/STAT and MAPK activation and the mechanisms that terminate or modulate these pathways. It emphasizes negative regulation by tyrosine phosphatases, SOCS feedback inhibitors and PIAS proteins, as well as cross-talk with other signalling cascades.
Key findings
- IL-6-type cytokines (IL-6, IL-11, LIF, OSM, CNTF, CT-1 and CLC) signal via gp130 homodimers or gp130–LIFR/OSMR heterodimers; all potently activate STAT3 and, to a lesser extent, STAT1 through gp130, while OSMR is the most potent activator of STAT5.
- Receptor activation requires more than simple dimerization: efficient gp130 activation by monoclonal antibodies required two distinct antibodies, with the minimal requirement being one intact antibody plus the Fab of a second; insertion of one to four alanines into the gp130 membrane-proximal intracellular region gave full activation only with wild-type and the +3A mutant, interpreted as an approx. 110° twist per alanine and approx. 330° for three.
- JAK1 is essential for IL-6 signalling; gp130, LIFR and OSMR bind JAK1, JAK2 and TYK2. JAK1 mobility is approx. 100-fold lower than that of a typical cytoplasmic protein, and gp130 residues including box1 prolines and Trp666 are critical for JAK binding, while W652A abrogates JAK1 activation without affecting JAK1 association.
- Signal termination involves SHP2 and SOCS3 at gp130 pTyr759, with SOCS3 binding gp130 peptides with slightly higher affinity than SHP2; SOCS1 and SOCS3 inhibit JAKs, PIAS1 inhibits STAT1 and PIAS3 inhibits STAT3. Reported half-lives include SOCS1 1.5 h, SOCS2 1 h, SOCS3 1.6 h, IL-6Rα 2–3 h, gp130 2.5 h, JAK1 3.2 h, JAK2 1.9 h, TYK2 2 h, STAT3α 8.5 h, STAT3β 4.5 h, STAT1 16 h and SHP-2 18–20 h.
Methods
- Narrative review of molecular mechanisms of IL-6-type cytokine signal transduction, focusing on advances made during the previous 5 years in receptor activation, JAK–receptor interactions, STAT activation, signal modulation and cross-talk.
- Synthesizes structural, mutagenesis, biochemical and in vivo findings from the literature; no primary experimental dataset is presented, and the text includes models and a table of half-lives drawn from cited studies.
Limitations
- The authors state that key structural data are still missing, including the structure and conformational states of the cytoplasmic parts of cytokine receptors, and that three-dimensional structures of JAKs and SOCS proteins would be extremely valuable.
- The authors state that mathematical models of this complexity suffer from a lack of sufficient quantitative experimental data, and that cross-talk and biological outcomes depend on cell type and differentiation state.
- Evident from the text: as a narrative review, it does not use a systematic search or meta-analysis, and it includes unpublished work/personal communications and unresolved conflicting findings, such as JNK versus p38 involvement in STAT3 Ser727 phosphorylation and the positive versus negative regulatory functions reported for STAT3β.
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Claims the paper makes
172 Sources not found · 17 Own interpretation · 16 No basis given · 7 Not checked yet · 2 Own result
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In the paper
“Human OSM has the exceptional capability to recruit two different receptor complexes.It forms both LIFR-gp130 and OSMR-gp130 heterodimers.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“LIF and OSM directly engage their signalling receptor subunits without requirement for additional α-receptor subunits (Figure 2) [4,6].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“Soluble forms of cytokine receptors in vivo are formed either by limited proteolysis (shedding) of membrane-bound receptors or by translation from an alternatively spliced mRNA [4].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“It has been demonstrated that sIL-6Rα potentiates the antagonistic activity of sgp130.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“In contrast with IL-6, and presumably also IL-11, where all the helices are straight, the A helix of LIF, OSM and CNTF is kinked [17,18].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“The minimal requirement for receptor activation is one intact antibody and the Fab (fragment antigen binding) of the second antibody.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptors at work: let's do the twist
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In the paper
“It has been shown that these domains are necessary for coupling ligand binding and signal transduction, since deletion of these domains leads to signalling incompetent receptors [36,37].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptors at work: let's do the twist
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“Thus in the homodimer two different binding epitopes of gp130 are involved in ligand recognition [23].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“The interaction sites predicted by mutagenesis studies have recently been confirmed by the X-ray structure of KSHV-IL-6 bound to a soluble gp130 fragment comprising the CBM and the Ig-like domain [24].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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“In contrast with the α-receptors, the receptors that initiate signal transduction have three additional membrane-proximal FNIII domains [4].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“This structural divergence might reflect differences in the mechanisms of receptor recruitment, since the straight cytokines signal via gp130 homodimers, whereas the kinked cytokines signal via LIFR-gp130 or OSMR-gp130 heterodimers.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“Of these, JAK1 plays an essential role, because in cells lacking JAK1 IL-6 signal transduction is greatly impaired [51,52,134].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptor-JAK interaction: more than just a rendez-vous
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In the paper
“This finding has been interpreted in a way that the bivalent intact antibody enforces receptor dimerization and the monovalent Fab adjusts the conformation required for JAK activation and downstream signalling [40].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptors at work: let's do the twist
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In the paper
“Some evidence has been provided that under certain circumstances gp130 and LIFR are degraded after internalization [30][31][32].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“While for gp130, the STATs were found to depend on a specific conformation in order to become phosphorylated, for the EpoR the receptor phosphorylation seems to be sensitive to changes in orientation.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptors at work: let's do the twist
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In the paper
“KSHV-IL-6 binds the gp130 homodimer in the absence of any α-receptor [16], but with lower affinity as compared with IL-6-IL-6Rα-gp130 ternary complexes.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“Internalization of gp130 seems to be independent from ligand binding [28], and is modulated by phosphorylation at Ser 782 [29] which is located adjacent to the dileucine motif.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“ErbB2 forms a complex with gp130 in an IL-6-dependent manner in prostate carcinoma cells [35].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“In certain cell types, a localization of gp130 in plasma membrane microdomains, such as lipid rafts and caveolae, has been observed [9][10][11].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“After secretion of the CLC-CLF-1 or CLC-CNTFRα complexes, signalling is dependent on CNTFRα and occurs via gp130-LIFR heterodimers.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > INTRODUCTION
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In the paper
“Constantinescu et al. [46] identified a hydrophobic motif in the EpoR membrane-proximal domain (Leu 253 , Ile 257 and Trp 258 ) which is conserved in many cytokine receptors and needs to be precisely orientated in order to promote signalling.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptors at work: let's do the twist
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In the paper
“PKCδ enhances the association of STAT3 with the receptor, which possibly involves the phosphorylation of Thr 890 of gp130 [67].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptor-JAK interaction: more than just a rendez-vous
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In the paper
“All IL-6-type cytokines potently activate STAT3, and to a minor extent STAT1 through their common receptor subunit gp130 [4].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Another face of JAKs: determination of the receptor's fate
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In the paper
“The Cterminal tyrosine kinase domain is preceded by a pseudokinase domain, which itself is devoid of catalytic activity, but regulates the activity of the kinase domain [3].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptor-JAK interaction: more than just a rendez-vous
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In the paper
“In the cases of LIFR and OSMR, STAT3 and STAT1, as well as STAT5, activation has been observed, with OSMR being the most potent activator of STAT5 [56].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Another face of JAKs: determination of the receptor's fate
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In the paper
“These results were confirmed by Chung et al. [105], who also observed that IL-6-induced STAT3 activation is MAPK independent, but sensitive to H7.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Serine phosphorylation
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In the paper
“Cdk9 (cyclin-dependent kinase 9) was also found to bind to gp130, and the association increased upon IL-6 stimulation of HEK 293 cells over-expressing gp130 and Cdk9 [66].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptor-JAK interaction: more than just a rendez-vous
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In the paper
“Deletion of these amino acids reduces IL-6-induced Hck kinase activity, ERK (extracellular-regulated kinase) activation, dephosphorylation of Pyk2 and proliferation of transfected pro-B Ba/F3 cells [65].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptor-JAK interaction: more than just a rendez-vous
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In the paper
“A conformational change in the SH2 domain may account for this dual specificity [91].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Another face of JAKs: determination of the receptor's fate
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In the paper
“The recruitment of STATs to the activated receptors has been shown to be mediated by their SH2 domain and requires the phosphorylation of receptor tyrosine motifs [74,[81][82][83].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Another face of JAKs: determination of the receptor's fate
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In the paper
“substitution of Trp 652 with alanine (W652A) within the box1 region has no effect on JAK1 association but abrogates JAK1 activation.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptor-JAK interaction: more than just a rendez-vous
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plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Mutations with similar consequences (no JAK activation in spite of JAK association) have been described for the EpoR [59], indicating that cytokine receptors in general contribute to the JAK-activation process.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptor-JAK interaction: more than just a rendez-vous
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Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
- Not matched
In the paper
“human fibrosarcoma cells lacking JAK1 express less OSMR at their surface compared with the parental cells, but transient transfection of JAK1 can again increase the amount of surface-expressed receptors [49].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Another face of JAKs: determination of the receptor's fate
What the sources say
- Not matchedcites [49]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
- Not matched
In the paper
“Box2 of gp130, a sequence dominated by hydrophobic amino acids followed by charged ones, contributes to JAK binding, presumably by increasing the affinity; a gp130 construct lacking box2 coprecipitates with JAK1 only when the kinase is over-expressed [55].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Receptor-JAK interaction: more than just a rendez-vous
What the sources say
- Not matchedcites [55]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
- Not matched
In the paper
“This leads to the formation of active STAT dimers, also shown to be mediated by their SH2 domains [90].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Another face of JAKs: determination of the receptor's fate
What the sources say
- Not matchedcites [90]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
It may state two separate claims as one.
- Not matched
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
“In response to IL-6, Gab1 is tyrosine phosphorylated and interacts subsequently with SHP2 and PI3K.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Activation of MAPK cascades: one tyrosine to make things more complicated
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.
It may state two separate claims as one.
In the paper
“A recent study [112] on STAT3 activation in response to EGF (epidermal growth factor) suggests that receptor-mediated endocytosis is required for shuttling of STAT3 from the plasma membrane to the perinuclear region.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > STAT nuclear translocation: not a one way ticket
What the sources say
- Not matchedcites [112]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- 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.
- Not matched
In the paper
“In the DNA-binding domain of STAT1, initially an NES was postulated that comprises residues 399-410 [108].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > STAT nuclear translocation: not a one way ticket
What the sources say
- Not matchedcites [108]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- 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.
- Not matched
In the paper
“Compared with the unmethylated protein, methylated STAT1 has a higher tendency to associate with DNA, since its interaction with PIAS (protein inhibitor of activated STATs) 1 (see the subsection below entitled 'PIAS -more than inhibitors of activated STATs?') seems to be weaker [106].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Methylation of STATs
What the sources say
- Not matchedcites [106]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgeddirect- 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.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“The family of IL-6-type cytokines not only activates ERK1/2, a MAPK known for cellular processes that maintain cell survival, but also the stress-activated members of the MAPK family: p38 and JNK [140-142] (Figure 6).”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Activation of MAPK cascades: one tyrosine to make things more complicated
What the sources say
- Not matchedcites [140]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [141]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [142]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Sensitivity to leptomycin suggests that nuclear export of STAT1 involves the nuclear export receptor CRM-1 that also acts in a Randependent manner [108,109].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > STAT nuclear translocation: not a one way ticket
What the sources say
- Not matchedcites [108]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [109]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
- Not matched
In the paper
“However, from an earlier study [113], it was concluded that nuclear translocation of STAT1 in response to IFNγ does not require cytoskeletal structures, such as actin filaments or microtubules.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > STAT nuclear translocation: not a one way ticket
What the sources say
- Not matchedcites [113]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- 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.
Probably not a substantial claim.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“According to the current view of the SHP2-dependent activation of MAPKs adopted from EGF and PDGF (platelet-derived growth factor) signal transduction, SHP2 links the Grb2-SOS (growthfactor-receptor-bound protein/Son of Sevenless) complex and/or Gab1 (Grb2-associated binder-1) to gp130 [127,129,130].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Activation of MAPK cascades: one tyrosine to make things more complicated
What the sources say
- Not matchedcites [127]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [129]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [130]
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.
- 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.
- Not matched
In the paper
“In response to IL-2, Epo, EGF, and PDGF, SOCS3 (suppressor of cytokine signalling 3) becomes tyrosine phosphorylated, and subsequently binds and inactivates Ras/GTPase-activating protein.This results in the inhibition of the GTPase activity of Ras, leading to a sustained Ras/GTP and MAPK activity [139].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Activation of MAPK cascades: one tyrosine to make things more complicated
What the sources say
- Not matchedcites [139]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
It may state two separate claims as one.
- Not matched
In the paper
“SHP2 is rapidly recruited to tyrosine-phosphorylated gp130 and becomes also phosphorylated in a JAK1-dependent manner [131].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Activation of MAPK cascades: one tyrosine to make things more complicated
What the sources say
- Not matchedcites [131]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
It may state two separate claims as one.
- Not matched
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
“Dimerization of IL-6-type cytokine receptors does not only lead to activation of the JAK/STAT-signalling pathway, but also to the induction of the MAPK cascade.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Activation of MAPK cascades: one tyrosine to make things more complicated
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.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Furthermore, nuclear accumulation of constitutively active STAT proteins is independent from endocytosis, because in these cases the STATs are not recruited to any plasma membrane receptor [110,114].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > STAT nuclear translocation: not a one way ticket
What the sources say
- Not matchedcites [110]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [114]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- 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.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“PIAS1 inhibits STAT1 signalling [179], but conversely enhances the transcriptional activity of nuclear hormone receptors [180].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > PIAS -more than inhibitors of activated STATs?
What the sources say
- Not matchedcites [179]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [180]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Whereas SHP2 modulates the amount and amplitude of STAT3 activity [131,158], PTPεC affects the kinetics of the onset of STAT3 activation [169].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Protein tyrosine phosphatases (PTPs): what goes up must come down
What the sources say
- Not matchedcites [131]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [158]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [169]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
It may state two separate claims as one.
- Not matched
In the paper
“It should be noted, however, that PI3K activation upon IL-6 treatment is observed in a cell-type specific manner; e.g.no significant Akt activation could be observed in IL-6treated HepG2 hepatoma cells [149].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Activation of the PI3K cascade: the lipid connection
What the sources say
- Not matchedcites [149]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedged- 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.
- Not matched
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
“This enzyme modifies certain phosphatidylinositides, so that the serine/threonine kinase protein kinase B/Akt is recruited to the plasma membrane, where it becomes activated through phosphorylation by PDK1 (phosphoinositide-dependent kinase-1).”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Activation of the PI3K cascade: the lipid connection
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.
It may state two separate claims as one.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Early results suggested the presence of a nuclear phosphatase which counteracts IFNγ -activated STAT1 and contributes to its nuclear export [121,173].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Protein tyrosine phosphatases (PTPs): what goes up must come down
What the sources say
- Not matchedcites [121]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [173]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgeddirect- 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.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Interaction of SHP2 with JAK1, JAK2 and TYK2, and phosphorylation of SHP2 by JAK1 and JAK2, have at least been shown to occur in vitro [131,162].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Protein tyrosine phosphatases (PTPs): what goes up must come down
What the sources say
- Not matchedcites [131]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [162]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgeddirect- 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.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“IL-6-induced activation of the PI3K/Akt pathway is involved in protection against apoptosis, as well as in enhanced proliferation of multiple myeloma cells [145][146][147].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Activation of the PI3K cascade: the lipid connection
What the sources say
- Not matchedcites [145]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [146]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [147]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
It may state two separate claims as one.
- Not matched
In the paper
“The cytoplasmic variant of PTPε, PTPεC, is expressed in haematopoietic cells and has been shown to selectively inhibit IL-6-induced gp130, JAK and STAT activation [168].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Protein tyrosine phosphatases (PTPs): what goes up must come down
What the sources say
- Not matchedcites [168]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
It may state two separate claims as one.
- Not matched
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
“On the other hand, the IL-6induced activation of the MAPK cascade is impaired by mutation of Tyr 759 within gp130, indicating that SHP2, as an adaptor, has a positive function on the activation of the MAPK cascade (as shown in Figure 1).”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Protein tyrosine phosphatases (PTPs): what goes up must come down
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.
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
“The family of PIAS comprises five mammalian members: PIAS1, PIAS3, PIASxα, PIASxβ, and PIASy.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > PIAS -more than inhibitors of activated STATs?
plain- 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
“Thus methylation not only supports STAT activity (by preventing PIAS association), but also promotes its inactivation by dephosphorylation.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Protein tyrosine phosphatases (PTPs): what goes up must come down
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.
In the paper
“Experiments in vivo underscore the in vitro findings in demonstrating that mice expressing gp130 lacking Tyr 759 display splenomegaly, lymphadenopathy and an enhanced acute-phase reaction [161].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Protein tyrosine phosphatases (PTPs): what goes up must come down
What the sources say
- Not matchedcites [161]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
- Not matched
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 differences suggest that signalling components requiring posttranslational modifications for their activation are long-lived, whereas the activity of short-lived proteins is regulated mainly at the transcriptional level.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Half-lives of signalling components: party as long as you live
hedgedcorrelational- 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.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Whereas the feedback inhibitors SOCS1, SOCS2 and SOCS3 are very short-lived, STAT1, STAT3α and SHP2 have slow turnover rates.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > Half-lives of signalling components: party as long as you live
What the sources say
- Not matchedcites [222]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [223]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- 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.
- Not matched
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
“The eight members of this family (CIS and SOCS1-SOCS7) contain a central SH2 domain, as well as a C-terminal domain called a SOCS box (Figure 4).”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > The SOCS family of feedback inhibitors: natural born terminators
plainn = 8- 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.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“For gp130, SOCS3 has been found to bind to the phosphotyrosine motif 759 [197,198], which is also the binding site for SHP2.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > The SOCS family of feedback inhibitors: natural born terminators
What the sources say
- Not matchedcites [197]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [198]
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.
- 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.
- Not matched
In the paper
“Phosphorylation occurs at two tyrosine residues (Tyr 204 and Tyr 221 ) within the SOCS box and phosphorylation of Tyr 221 recruits p120 RasGAP leading to sustained ERK activation [139].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > The SOCS family of feedback inhibitors: natural born terminators
What the sources say
- Not matchedcites [139]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Other reports, however, suggest that elongin C binding can stabilize SOCS1 and that the disruption of the interaction leads to proteasomal degradation of SOCS1 [206,215].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > The SOCS family of feedback inhibitors: natural born terminators
What the sources say
- Not matchedcites [206]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [215]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgeddirect- 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. It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Expression of SOCS proteins was found to be rapidly up-regulated by IL-6 (CIS, SOCS1, SOCS2 and SOCS3), LIF (CIS, SOCS1, SOCS2 and SOCS3), IL-11 (SOCS3) and OSM (CIS, SOCS1 and SOCS3) [32,190,192,193].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > The SOCS family of feedback inhibitors: natural born terminators
What the sources say
- Not matchedcites [32]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [190]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [192]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
It may state two separate claims as one.
- Not matched
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
“As SOCS proteins are induced via the JAK/STAT pathway and subsequently inhibit STAT-mediated signal transduction, they are acting as classical feedback inhibitors.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > The SOCS family of feedback inhibitors: natural born terminators
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.
In the paper
“These phosphotyrosine residues may be part of an activated receptor or the tyrosine-phosphorylated C-terminal tail of SHP2 (from [156]).”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > PERSPECTIVES
What the sources say
- Not matchedcites [156]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- 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. It may state two separate claims as one.
- Not matched
None of the sources cited for this claim have been checked yet.
In the paper
“FKHR specifically enhanced the activity of STAT3-dependent promoters, such as the α 2 M promoter, but not that of a STAT5-responsive promoter.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > STAT action within the transcriptosome: where transcription factors gather
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.
It may state two separate claims as one.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Other signalling pathways have been shown to induce stabilization of cytokine mRNAs as well: the JNK pathway induces stabilization of the short-lived IL-2 mRNA [219], and PI3K activation induces stabilization of IL-3 mRNA [220].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > PERSPECTIVES
What the sources say
- Not matchedcites [219]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [220]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- 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.
- Not matched
In the paper
“PI3K activation induces stabilization of IL-3 mRNA [220]”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > PERSPECTIVES
What the sources say
- Not matchedcites [220]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- 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.
- Not matched
In the paper
“The nuclear receptor co-repressor SMRT (silencing mediator of retinoic and thyroid hormone receptors) is a potential binding partner for STAT5 and represses STAT5-dependent transcription [255].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > STAT action within the transcriptosome: where transcription factors gather
What the sources say
- Not matchedcites [255]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
- Not matched
In the paper
“Furthermore, FKHR and STAT3 can be co-immunoprecipitated and co-localize in the nucleus of IL-6-treated HepG2 cells [149].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > STAT action within the transcriptosome: where transcription factors gather
What the sources say
- Not matchedcites [149]
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.
- 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.
- Not matched
In the paper
“the JNK pathway induces stabilization of the short-lived IL-2 mRNA [219]”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > PERSPECTIVES
What the sources say
- Not matchedcites [219]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- 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.
- Not matched
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
“Interestingly, an EZI mutant predominantly localized in the cytoplasm inhibited nuclear localization of STAT3, as well as STAT3-mediated transactivation.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > STAT action within the transcriptosome: where transcription factors gather
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.
In the paper
“Interestingly, Nmi itself is induced by IL-2 and IFNγ , indicating a positive feedback loop within this signal transduction.”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > STAT action within the transcriptosome: where transcription factors gather
What the sources say
- Not matchedcites [253]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgeddirect- 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.
- Not matched
In the paper
“This interaction is further modulated by Nmi (N-Myc interactor) which augments CBP recruitment to STAT1 and STAT5, and potentiates IL-2 and IFNγ signalling [253].”
§ Principles of interleukin (IL)-6-type cytokine signalling and its regulation 1 > STAT action within the transcriptosome: where transcription factors gather
What the sources say
- Not matchedcites [253]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
It may state two separate claims as one.
- Not matched
The authors state this as an assumption.
The membrane-proximal FNIII domains bridge the ~9 nm distance between the CBM C-termini so that the cytoplasmic parts are close enough to become activated by associated JAKs.
“The membrane-proximal FNIII domains might bridge this distance so that the cytoplasmic parts are in close enough proximity to become activated by the associated JAKs (Figure 5).This assumption is supported by a recent study on the role of the gp130 FNIII domains for heterodimerization with the LIFR [38].”
The paper relies on this without support.
gp130 is ubiquitously expressed.
“Although gp130 is ubiquitously expressed, the number of cells that respond to a certain IL-6-type cytokine is limited, since the expression of the other receptor subunits, especially of the α-receptors, is more restricted and tightly regulated.”
The paper relies on this without support.
IL-6-type cytokines form a subfamily of helix bundle cytokines.
“IL-6-type cytokines form a subfamily of the helix bundle cytokines.”
The paper relies on this without support.
All IL-6-type cytokines comprise four long α-helices A-D arranged in an up-up-down-down topology.
“All IL-6-type cytokines comprise four long α-helices termed A, B, C and D, which are arranged in a way that leads to an up-up-down-down topology (Figure 3).”
The paper relies on this without support.
Each receptor contains at least one cytokine-binding module (CBM) comprising two FNIII domains.
“Each receptor contains at least one cytokine-binding module (CBM) that comprises two FNIII-domains.”
The paper relies on this without support.
JAKs bind to the membrane-proximal region of cytokine receptors, which contains conserved box1 and box2 motifs.
“JAKs bind to the membrane-proximal region of cytokine receptors, which contains conserved so-called box1 and box2 motifs.”
The paper relies on this without support.
The N-terminal region of JAKs comprises a FERM domain crucial for receptor association.
“The N-terminal region of JAKs comprises a FERM (fourpoint-one, ezrin, radixin and moesin) domain which is crucial for receptor association.”
The paper relies on this without support.
The STAT family encompasses seven mammalian members.
“The STAT family of transcription factors encompasses seven mammalian members, designated STAT1, -2, -3, -4, -5a, -5b and -6.”
The paper relies on this without support.
In response to IL-6 stimulation, cytoplasmic STAT3 rapidly accumulates in the nucleus.
“In response to IL-6 stimulation, cytoplasmic STAT3 rapidly accumulates in the nucleus.”
The paper relies on this without support.
Nuclear accumulation is triggered by STAT dimerization in response to tyrosine phosphorylation.
“Nuclear accumulation is triggered by STAT dimerization in response to tyrosine phosphorylation.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“IL-6Rα expression is normally associated with hepatocytes and leukocytes but has also been described in cancer cells, including PDAC.”
From Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells (2024) · cites this paper as [40]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The cytokine IL-6 triggers multiple downstream responses, including metabolic regulation.”
From Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells (2024) · cites this paper as [40]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“IL-6, which was discovered in 1986 (27), is a pleiotropic cytokine involved not only in immune responses but also in inflammation, hematopoiesis, bone metabolism, embryonic development and other fundamental processes (1, 21, 28–32).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [30]
Experimental — accuracy not yet measured
Citations
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Cited by
Sorted by citations
Items 501–600 of 3,269
LIF-Dependent Signaling: New Pieces in the Lego
Mathieu, M.-E., Saucourt, C., Mournetas, V., Gauthereau, X., Thézé, N., Praloran, V., Thiébaud, P., & Bœuf, H. (2011) · Stem Cell Reviews and Reports · doi:10.1007/s12015-011-9261-7 · Cited by 96
Cytokine Control of Adult Neural Stem Cells
Bauer, Š. (2009) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.03986.x · Cited by 90
Interleukin-6 in renal disease and therapy
Jones, S. A., Fraser, D. J., Fielding, C. A., & Jones, G. W. (2014) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfu233 · Cited by 94
Huynh, P. T., Beswick, E. J., Coronado, Y. A., Johnson, P. R., O’Connell, M. R., Watts, T. L., Singh, P., Qiu, S., Morris, K. T., Powell, D. W., et al. (2015) · International Journal of Cancer · doi:10.1002/ijc.29939 · Cited by 96
“This interaction results in homodimerization of gp130, which then initiates signaling trough Janus kinases (JAKs).(4,5) IL-6 is known to act in a paracrine and autocrine manner on diverse target cells and has been Key words: CD901 fibroblasts, colorectal cancer, inflammation, IL-”
BackgroundMethodProinflammatory Cytokine IL‐6 and JAK‐STAT Signaling Pathway in Myeloproliferative Neoplasms
Čokić, V. P., Ajtić, O. M., Beleslin‐Čokić, B. B., Marković, D. C., Kovačić, M. V., Diklić, M., Kraguljac‐Kurtović, N., Damjanovic, S. S., Milenković, P., Gotić, M., et al. (2015) · Mediators of Inflammation · doi:10.1155/2015/453020 · Cited by 92
“All IL-6-type cytokines potently activate STAT3 and to a minor extent STAT1, while SOCS3 is the primary inhibitor of IL6 signaling [2, 3].”
BackgroundLiang, Z., Wu, G., Fan, C., Xu, J., Jiang, S., Yan, X., Di, S., Ma, Z., Hu, W., & Yang, Y. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.11.001 · Cited by 92
Chen, D. S., Soen, Y., Stuge, T. B., Lee, P. P., Weber, J. S., Brown, P. O., & Davis, M. M. (2005) · PLoS Medicine · doi:10.1371/journal.pmed.0020265 · Cited by 91
Dewulf, M., Köster, D., Sinha, B., de Lesegno, C. V., Chambon, V., Bigot, A., Bensalah, M., Négroni, E., Tardif, N., Podkalicka, J., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09405-5 · Cited by 96
Hou, T., Ray, S., Lee, C., & Brasier, A. R. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m805941200 · Cited by 91
Yang, R., Lirussi, D., Thornton, T. M., Jelley-Gibbs, D. M., Diehl, S. A., Case, L. K., Madesh, M., Taatjes, D. J., Teuscher, C., Haynes, L., et al. (2015) · eLife · doi:10.7554/elife.06376 · Cited by 91
“DOI: 10.7554/eLife.06376 1 of 22 IL-6 binds to its membrane receptor, which triggers signaling through gp130, a common transducer that activates Jak/Stat3 and Ras/MAPK pathways in T cells (Boulanger et al., 2003; Heinrich et al., 2003; Kishimoto, 2005).”
BackgroundInfluentialClahsen, T., & Schaper, F. (2008) · Journal of Leukocyte Biology · doi:10.1189/jlb.0308178 · Cited by 91
Self-citationDiscovery of Potent and Selective Pyrazolopyrimidine Janus Kinase 2 Inhibitors
Hanan, E. J., van Abbema, A., Barrett, K., et al. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm3012239 · Cited by 91
Perry, C. J., Blake, P., Buettner, C., Papavassiliou, E. D., Schain, A. J., Bhasin, M., & Burstein, R. (2016) · Annals of Neurology · doi:10.1002/ana.24665 · Cited by 94
Rega‐Kaun, G., Kaun, C., Weiss, T. W., Demyanets, S., Zorn, G., Kastl, S., Steiner, S., Seidinger, D., Kopp, C. W., Frey, M., et al. (2005) · Circulation · doi:10.1161/01.cir.0000161823.55935.be · Cited by 91
Weigert, C., Hennige, A. M., Brodbeck, K., Häring, H. U., & Schleicher, E. D. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00448.2004 · Cited by 94
“Our finding that IL-6-induced phosphorylation of Ser(473) is wortmannin sensitive is well in line with previous reports demonstrating the activation of the PI 3-kinase cascade by IL-6 (3, 9).”
BackgroundResultHowlett, M., Giraud, A. S., Lescesen, H., Jackson, C. B., Kalantzis, A., van Driel, I. R., Robb, L. G., der Hoek, M. B. V., Ernst, M., Minamoto, T., et al. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.12.003 · Cited by 91
IL-6 and TNF-α serum levels are associated with early death in community-acquired pneumonia patients
Bacci, M. R., Leme, R. C. P., Zing, N. P. C., Murad, N., Adami, F., Hinnig, P. F., Feder, D., Chagas, A. C. P., & Fonseca, F. L. A. (2015) · Brazilian Journal of Medical and Biological Research · doi:10.1590/1414-431x20144402 · Cited by 92
“Brazilian Journal of Medical and Biological Research (2015) 48(5): 427-432, http://dx.”
BackgroundChen, W., Xia, T., Wang, D., Huang, B., Zhao, P., Wang, J., Qu, X., & Li, X. (2016) · Oncotarget · doi:10.18632/oncotarget.11515 · Cited by 90
“In addition, IL-6 activated the AKT, p38MAPK and ERK1/2 signaling pathway [39].”
BackgroundInterleukin-6 in atherosclerosis: atherogenic or atheroprotective?
Reiss, A. B., Siegart, N. M., & Leon, J. D. (2017) · Clinical Lipidology · doi:10.1080/17584299.2017.1319787 · Cited by 94
Lupardus, P. J., Skiniotis, G., Rice, A. J., et al. (2011) · Structure · doi:10.1016/j.str.2010.10.010 · Cited by 90
“Second, gp130 can homodimerize or heterodimerize with a second gp130 family receptor (LIFR, OSMR, TCCR) depending on the cytokine encountered (Heinrich et al., 2003).”
BackgroundCharacterization of the Signaling Capacities of the Novel gp130-like Cytokine Receptor*
Dreuw, A., Radtke, S., Pflanz, S., Lippok, B., Heinrich, P., & Hermanns, H. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m401122200 · Cited by 87
Self-citationEffects of physical activity upon the liver
Shephard, R. J., & Johnson, N. A. (2014) · European Journal of Applied Physiology · doi:10.1007/s00421-014-3031-6 · Cited by 93
Rawlings, J. S., Rennebeck, G., Harrison, S. M. W., Xi, R., & Harrison, D. A. (2004) · BMC Cell Biology · doi:10.1186/1471-2121-5-38 · Cited by 90
“In mammals, there are multiple points of cross-talk between the JAK and EGFR/MAPK signaling pathways [3,38-40].”
BackgroundMagyari, L. (2014) · World Journal of Orthopedics · doi:10.5312/wjo.v5.i4.516 · Cited by 92
The Role of Interleukin 6 in Periodontitis and Its Complications
Mazurek−Mochol, M., Bonsmann, T., Mochol, M., Poniewierska-Baran, A., & Pawlik, A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25042146 · Cited by 104
“…signaling pathways and acts via signal transducers, like glycoprotein 130 (gp130), LIF receptor and OSM receptor, leading to the activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) cascade, as well as the mitogen-activated protein kinase (MAPK) cascade [12].”
BackgroundChapter 7 Neuroendocrine–Immune Interactions in Teleost Fish
Kemenade, B. M. L. V.-V., Stolte, E. H., Metz, J. R., & Chadzińska, M. (2009) · Fish physiology · doi:10.1016/s1546-5098(09)28007-1 · Cited by 130
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Oncostatin M Inhibits Adipogenesis through the RAS/ERK and STAT5 Signaling Pathways
Miyaoka, Y., Tanaka, M., Naiki, T., & Miyajima, A. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m606089200 · Cited by 89
Su, J.-L., Lai, K.-P., Chen, C., et al. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-0188 · Cited by 89
“Specifically, the IL-6/IL-6R complex initiates homodimerization of the ubiquitously expressed gp130 (h chain), activates a cytoplasmic tyrosine kinase bound to gp130, and then triggers Janus-activated kinase/signal transducers and activators of transcription (STAT), Ras/mitogen-activated protein kinase (MAPK), and pho…”
BackgroundPark, J., Lee, J. J., Lim, M., Kim, E., Kim, S.-M., Ryu, J.-G., Lee, J. H., Kwok, S.-K., Park, K.-S., Kim, H., et al. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1300514 · Cited by 88
“Moreover, IL-6–induced JAK family members activate JAK/STAT and MAPK cascades (14).”
BackgroundBourdi, M., Eiras, D., Holt, M. P., Webster, M. R., Reilly, T., Welch, K., & Pohl, L. (2007) · Chemical Research in Toxicology · doi:10.1021/tx060228l · Cited by 80
Doremus‐Fitzwater, T. L., Gano, A., Paniccia, J. E., & Deak, T. (2015) · Physiology & Behavior · doi:10.1016/j.physbeh.2015.02.032 · Cited by 93
“Thus, these results suggest that intoxication-related increases in IL-6 mRNA expression are a consistent result of ethanol exposure in adults, with IκBα increases implicating IL-6 signaling-related interaction with the NF-κB signaling cascade via phosphatidylinositide 3-kinase (PI3K) or other pathways [49].”
BackgroundSun, W., Liu, D., Li, W., et al. (2014) · International Journal of Oncology · doi:10.3892/ijo.2014.2323 · Cited by 88
“While gp130 is ubiquitously expressed by cells, the expression of IL-6R is restricted in selected cells (12).”
BackgroundRole of mTOR in neuroprotection and axon regeneration after inflammatory stimulation
Leibinger, M., Andreadaki, A., & Fischer, D. (2012) · Neurobiology of Disease · doi:10.1016/j.nbd.2012.01.004 · Cited by 89
“CNTF and LIF activate several signaling pathways, including the JAK/STAT3, PI3K/Akt and MAPK/ERK-signaling pathways (Heinrich et al., 2003).”
BackgroundMüller, S., Chakrapani, P. S. B., Schwegler, H., Hofmann, H., & Kirsch, M. (2008) · Stem Cells · doi:10.1634/stemcells.2008-0234 · Cited by 88
Ogiya, D., Liu, J., Ohguchi, H., Kurata, K., Samur, M. K., Tai, Y.-T., Adamia, S., Ando, K., Hideshima, T., & Anderson, K. C. (2020) · Blood · doi:10.1182/blood.2019004332 · Cited by 92
Savvatis, K., Müller, I., Fröhlich, M., Pappritz, K., Zietsch, C., Hamdani, N., Grote, K., Schieffer, B., Klingel, K., Linthout, S. V., et al. (2014) · Basic Research in Cardiology · doi:10.1007/s00395-014-0449-2 · Cited by 87
“IL-6 is centrally involved in the acute phase inflammatory response, recruiting neutrophils and monocytes in the inflammatory area [11].”
BackgroundHaldar, R., Shaashua, L., Lavon, H., Lyons, Y. A., Zmora, O., Sharon, E., Birnbaum, Y., Allweis, T. M., Sood, A. K., Barshack, I., et al. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.05.014 · Cited by 88
The Interplay of Notch Signaling and STAT3 in TLR-Activated Human Primary Monocytes
Hildebrand, D., Uhle, F., Sahin, D., et al. (2018) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2018.00241 · Cited by 87
“Furthermore, we state that Notch-boosted IL-6 and the subsequent autocrine IL-6 receptor signaling, that is known to activate JAK/STAT pathway (Heinrich et al., 2003) stabilize STAT3 activation.”
BackgroundTraumatic inflammatory response: pathophysiological role and clinical value of cytokines
Li, R., Ye, J. J., Gan, L., Zhang, M., Sun, D., Li, Y., Wang, T., & Chang, P. (2023) · European Journal of Trauma and Emergency Surgery · doi:10.1007/s00068-023-02388-5 · Cited by 87
“Subsequently, IL-6 can play an anti-inflammatory role by downregulating pro-inflammatory factors, including IL-1 and TNF-α [44, 45].”
Human monocyte activation by biologic and biodegradable meshes in vitro
Orenstein, S. B., Qiao, Y., Kaur, M., Klueh, U., Kreutzer, D. L., & Novitsky, Y. W. (2009) · Surgical Endoscopy · doi:10.1007/s00464-009-0664-3 · Cited by 86
Serrano-Marco, L., Barroso, E., Kochairi, I. E., Palomer, X., Michalik, L., Wahli, W., & Vázquez‐Carrera, M. (2011) · Diabetologia · doi:10.1007/s00125-011-2401-4 · Cited by 87
“(STAT3) [14].”
Regulation of systemic iron homeostasis: how the body responds to changes in iron demand
Anderson, G. J., Darshan, D., Wilkins, S. J., & Frazer, D. M. (2007) · BioMetals · doi:10.1007/s10534-006-9030-2 · Cited by 87
“IL6 signals via the JAK/STAT signalling pathway ( Heinrich et al. 2003 ).”
BackgroundMacha, M. A., Rachagani, S., Gupta, S., Pai, P., Ponnusamy, M. P., Batra, S. K., & Jain, M. (2013) · Cancer Letters · doi:10.1016/j.canlet.2013.07.037 · Cited by 87
“The rabbit polyclonal antibodies against cleaved caspase-9 (Asp330), pSTAT3 (Ser705)/STAT3, pSTAT1 (Ser-727)/ STAT1, pFAK (Tyr 925, Tyr 576/577)/tFAK, pSrc/Src (Tyr 416), xIAP were obtained from Cell Signaling (St. Louis, MO, USA).”
BackgroundInfluentialTLR9 Signaling in the Tumor Microenvironment Initiates Cancer Recurrence after Radiotherapy
Gao, C., Kozłowska, A. K., Nechaev, S., Li, H., Zhang, Q., Hossain, D. M. S., Kowolik, C. M., Chu, P. G., Swiderski, P. M., Diamond, D. J., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-13-1314 · Cited by 89
“IL-6 is known for inducing rapid STAT3 phosphorylation through the IL-6R–associated Janus family kinases, primarily Jak1 rather than Jak2 or Tyk2 (32).”
Orabona, C., Belladonna, M. L., Vacca, C., Bianchi, R., Fallarino, F., Volpi, C., Gizzi, S., Fioretti, M. C., Grohmann, U., & Puccetti, P. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.11.6582 · Cited by 88
“Not only does the feedback inhibitor SOCS3 attenuate IL-6 signaling (2) but up-regulation of SOCS3 by IL-6 may be responsible for inhibition of STATdependent signaling by IFNs (3).”
BackgroundDiao, Y., Guo, X. H., Jiang, L., Wang, G., Zhang, C., Wan, J., Jin, Y. J., & Wu, Z. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.494716 · Cited by 86
Malsch, P., Andratsch, M., Vogl, C., Link, A. S., Alzheimer, C., Brierley, S. M., Hughes, P. A., & Kress, M. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.5161-13.2014 · Cited by 86
“The cytokines act on their target cells via heteromeric receptor complexes that require glycoprotein 130 (gp130) as signal transducer subunit (Heinrich et al., 2003).”
BackgroundMethodInfluentialThe role of IL-6 in coronavirus, especially in COVID-19
Wang, X., Tang, G., Liu, Y., Zhang, L., Chen, B., Han, Y., Fu, Z., Wang, L., Hu, G., Ma, Q., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1033674 · Cited by 92
TRIM8 modulates STAT3 activity through negative regulation of PIAS3
Okumura, F., Matsunaga, Y., Katayama, Y., Nakayama, K. I., & Hatakeyama, S. (2010) · Journal of Cell Science · doi:10.1242/jcs.068981 · Cited by 86
“Since many cytokine receptors do not have intrinsic tyrosine-kinase activity, ligand engagement leads to the activation of receptorassociated tyrosine kinases, which are usually members of the Janus kinase (JAK) family (Darnell, 1998; Heinrich et al., 2003; Stark et al., 1998; Yu et al., 2007).”
BackgroundIDH2 deficiency promotes mitochondrial dysfunction and cardiac hypertrophy in mice
Ku, H. J., Ahn, Y., Lee, J. H., Park, K. M., & Park, J. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.12.018 · Cited by 86
Kong, L.-Y., Wei, J., Sharma, A. K., Barr, J., Abou-Ghazal, M. K., Fokt, I., Weinberg, J. S., Rao, G., Grimm, E. A., Priebe, W., et al. (2008) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-008-0618-y · Cited by 87
“patient’s immune system, promotes tumor aggression, malignancy, and metastasis [12, 23, 30, 33].”
Frisullo, G., Massimiliano Mirabella, A., Angelucci, F., Caggiula, M., Roberta Morosetti, A., Sancricca, C., Patanella, A. K., Nociti, V., Iorio, R., Bianco, A. D., et al. (2007) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2007.08.008 · Cited by 86
“…by the long signalling form of its receptor (ObRb), a member of the class I cytokine receptor family, which includes receptors for IL-6, IL-11, leukaemia inhibitory factor, granulocyte-colony stimulating factor, ciliary neurotrophic factor, oncostatin M and cardiotrophin-1 (Heinrich et al., 2003).”
BackgroundSignal Transduction in Trophoblast Invasion
Fitzgerald, J. S., Busch, S., Wengenmayer, T., Foerster, K., de la Motte, T., Poehlmann, T. G., & Markert, U. R. (2005) · KARGER eBooks · doi:10.1159/000087834 · Cited by 89
Review: LIF and IL11 in trophoblast-endometrial interactions during the establishment of pregnancy
Dimitriadis, E., Menkhorst, E. M., Salamonsen, L. A., & Paiva, P. (2010) · Placenta · doi:10.1016/j.placenta.2009.12.027 · Cited by 86
Xiao, Y., Sun, X., Yang, X., Zhang, J., Xue, Q., Cai, B., & Zhou, Y. (2009) · Fertility and Sterility · doi:10.1016/j.fertnstert.2009.03.012 · Cited by 85
Kox, M., van Velzen, J. F., Pompe, J. C., Hoedemaekers, C., van der Hoeven, J. G., & Pickkers, P. (2009) · Biochemical Pharmacology · doi:10.1016/j.bcp.2009.06.096 · Cited by 85
“The upregulation of STAT5A and the blockade of LPS-induced downregulation of STAT5B by GTS-21 further indicate JAK2 activity as STAT5 is also activated by JAK2 in monocytes [49].”
BackgroundInfluentialGu, Y., He, M., Zhou, X., Liu, J., Hou, N., Tan, B., Zhang, Y., Li, T., & Chen, J. (2016) · Scientific Reports · doi:10.1038/srep18587 · Cited by 89
The role of interleukin-6 in rheumatoid arthritis-associated osteoporosis
Edwards, C., & Williams, E. (2010) · Osteoporosis International · doi:10.1007/s00198-010-1192-7 · Cited by 90
“The actions of IL-6 are mediated through an interaction between its non-signalling α-receptor, IL-6 receptor (IL6R) and the signal transducing receptor, glycoprotein (gp) 130 [31, 32] (Fig.”
BackgroundInterleukin-6 inhibition in the management of non-infectious uveitis and beyond
Karkhur, S., Hasanreisoğlu, M., Vigil, E. M., Halim, M. S., Hassan, M., Plaza, C., Nguyen, N. V., Afridi, R., Tran, A. N. T., Diana, V., et al. (2019) · Journal of Ophthalmic Inflammation and Infection · doi:10.1186/s12348-019-0182-y · Cited by 86
“With the exception of IL-31, all IL-6 type cytokines share the membrane glycoprotein gp130 as a common beta receptor and signal transducer subunit [24, 25].”
BackgroundSARS-CoV-2 Disrupts Proximal Elements in the JAK-STAT Pathway
Chen, D. W., Khan, N., Close, B. J., Goel, R. K., Blum, B. C., Tavares, A. H., Kenney, D., Conway, H. L., Ewoldt, J. K., Chitalia, V. C., et al. (2021) · Journal of Virology · doi:10.1128/jvi.00862-21 · Cited by 81
“Finally, SARS-CoV-2-infected cells exhibited strong desensitization to IL-6, a proinflammatory cytokine that also signals through JAK proteins (26) (Fig.”
BackgroundSystemic effects of IL-6 blockade in rheumatoid arthritis beyond the joints
Jarlborg, M., & Gabay, C. (2021) · Cytokine · doi:10.1016/j.cyto.2021.155742 · Cited by 90
Redox signaling in the pancreas in health and disease
Sastre, J., Pérez, S., Sabater-Orti, L., & Rius‐Pérez, S. (2024) · Physiological Reviews · doi:10.1152/physrev.00044.2023 · Cited by 101
Pons, J., Sauleda, J., Regueiro, V., Santos, C., López, M., Ferrer, J. M., Agustí, A. G. N., & Bengoechea, J. A. (2006) · Respiratory Research · doi:10.1186/1465-9921-7-64 · Cited by 85
“This could be achieved by blocking the effect of IL-6 on TLR-2 expression using an antibody against the receptor of this cytokine [44,45] or blocking the IL-6 intracellular signalling pathway through the induction of SOCS3, an endogenous signalling repressor of cytokine signals [44,46].”
MethodThe gp130 Receptor Cytokine Family: Regulators of Adipocyte Development and Function
White, U. A., & Stephens, J. M. (2011) · Current Pharmaceutical Design · doi:10.2174/138161211795164202 · Cited by 84
“These cytokines regulate a variety of complex biological processes, including hematopoiesis, immune response, inflammation, proliferation, differentiation, mammalian reproduction, cardiovascular action, and neuronal survival [reviewed in [2]).”
BackgroundTGF‐β down‐regulates IL‐6 signaling in intestinal epithelial cells: Critical role of SMAD‐2
Walia, B. S., Wang, L.-X., Merlin, D., & Sitaraman, S. (2003) · The FASEB Journal · doi:10.1096/fj.02-1211fje · Cited by 95
IL-6 Trans–Signaling Links Inflammation with Angiogenesis in the Peritoneal Membrane
Catar, R. A., Witowski, J., Zhu, N., Lücht, C., Soria, A. D., Fernandez, J. U., Chen, L., Jones, S. A., Fielding, C. A., Rudolf, A. H., et al. (2016) · Journal of the American Society of Nephrology · doi:10.1681/asn.2015101169 · Cited by 85
“8 As SP4 has not been typically associated with IL-6 signal transduction, we examined the activation of STAT3, a key regulator of IL-6 signaling.(23) Indeed, stimulation of HPMC with IL6+sIL-6R resulted in a time-dependent induction of STAT3, but also of SP4 mRNA (Fig.”
BackgroundJohan, M. F., Bowen, D., Frew, M. E., et al. (2005) · British Journal of Haematology · doi:10.1111/j.1365-2141.2005.05412.x · Cited by 84
“The JAK/STAT pathway, for example, is subject to negative regulation by three protein families; the SH2-containing phosphatases (SHP), the suppressors of cytokine signalling (SOCS) and the protein inhibitors of activated STATs (PIAS) (reviewed in Heinrich et al, 2003).”
BackgroundRadtke, S., Haan, S., Jörissen, A., Hermanns, H. M., Diefenbach, S., Smyczek, T., de Leur, H. S.-V., Heinrich, P. C., Behrmann, I., & Haan, C. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m500822200 · Cited by 84
Self-citationBiomarkers of aging in frailty and age-associated disorders: State of the art and future perspective
Salvioli, S., Basile, M. S., Bencivenga, L., Carrino, S., Conte, M., Damanti, S., LORENZO, R. D., Fiorenzato, E., Gialluisi, A., Ingannato, A., et al. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.102044 · Cited by 91
“activation of intracellular signaling pathways (the so-called classical signaling), leading to IL-6-dependent gene expression and IL-6-dependent cellular responses such as proliferation, migration, expression of other molecules or metabolic changes (Heinrich et al., 2003).”
The Complex Role of STAT3 in Viral Infections
Kuchipudi, S. V. (2015) · Journal of Immunology Research · doi:10.1155/2015/272359 · Cited by 88
“Because only STAT3 dimers bind to DNA, the nuclear PTP TC45 may be important in the termination of STAT3-mediated transcriptional activation [51, 53].”
BackgroundPaiva, P., Salamonsen, L. A., Manuelpillai, U., Walker, C., Tapia-Pizarro, A., Wallace, E. M., & Dimitriadis, E. (2007) · Endocrinology · doi:10.1210/en.2007-0517 · Cited by 83
Lim, C. P., Phan, T. T., Lim, I. J., & Cao, X. (2008) · Journal of Investigative Dermatology · doi:10.1038/jid.2008.337 · Cited by 83
“Both are members of the IL-6-type cytokine family, which utilizes the gp130 receptor for signaling to activate the JAK/STAT and MAPK pathways (Heinrich et al., 2003).”
BackgroundProtective effect of Arbutus unedo aqueous extract in carrageenan-induced lung inflammation in mice
Mariotto, S., Esposito, E., Paola, R. D., Ciampa, A. R., Mazzon, E., de Prati, A. C., Darra, E., Vincenzi, S., Cucinotta, G., & Caminiti, R. (2007) · Pharmacological Research · doi:10.1016/j.phrs.2007.12.005 · Cited by 83
Storer, M. A., Gallagher, D., Fatt, M. P., Simonetta, J. V., Kaplan, D. R., & Miller, F. D. (2018) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.03.008 · Cited by 83
“Although IL-6 is the only IL-6R ligand, this cytokine is a member of a growth factor family that signals through a receptor complex involving gp130 and various ligand-specific receptor components (Heinrich et al., 2003).”
BackgroundXiao, Y., Wang, J., Yan, W., Zhou, Y., Chen, Y., Zhou, K., Wen, J., Wang, Y., & Cai, W. (2014) · Journal of Hepatology · doi:10.1016/j.jhep.2014.10.033 · Cited by 82
“IL-6 leads to the recruitment of the signal transducing subunit gp130 and then subsequently activates signal transducer and activator of transcription 3 (STAT3) [11,12].”
BackgroundWang, X., Li, Y., Dai, Y., Liu, Q., Ning, S., Liu, J., Shen, Z., Zhu, D., Jiang, F., Zhang, J., et al. (2016) · Scientific Reports · doi:10.1038/srep36796 · Cited by 84
Long non-coding RNAs and JAK/STAT signaling pathway regulation in colorectal cancer development
Ghasemian, A., Omear, H. A., Mansoori, Y., Mansouri, P., Deng, X., Darbeheshti, F., Zarenezhad, E., Kohansal, M., Pezeshki, B., Wang, Z., et al. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2023.1297093 · Cited by 84
“STATs 1, 2, 3, and 5 enter the nucleus and control the interferon gene transcription.”
BackgroundSánchez‐Infantes, D., White, U. A., Elks, C. M., Morrison, R. F., Gimble, J. M., Considine, R. V., Ferrante, A. W., Ravussin, É., & Stephens, J. M. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-3555 · Cited by 84
“E222 Sanchez-Infantes et al Adipose Oncostatin M in Obesity and Diabetes J Clin Endocrinol Metab, February 2014, 99(2):E217–E225”
BackgroundInfluentialThe resolution of inflammation and cancer
Rodríguez‐Vita, J., & Lawrence, T. (2009) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2009.11.006 · Cited by 83
“is associated with the inhibition of inflammation [28,29].”
BackgroundLee, J., Kim, H. S., Yang, C., Kyeong, H., Choi, J.-M., Hwang, D.-E., Yuk, J., Park, K., Kim, Y., Lee, S., et al. (2014) · Molecular Therapy · doi:10.1038/mt.2014.59 · Cited by 83
Ji, M.-L., Lü, J., Shi, P., Zhang, X.-J., Wang, S.-Z., Chang, Q., Chen, H., & Wang, C. (2015) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2753 · Cited by 82
“IL-6 leads to the recruitment of the signal transducing subunit gp130 and then subsequently activates signal transducer and activator of transcription 3 (STAT3).((15)) However, the precise mechanism of IL-6–mediated ECM in IDD has not been fully characterized.”
BackgroundCoelho-Santos, V., Gonçalves, J., Fontes-Ribeiro, C., & Silva, A. P. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-103 · Cited by 81
“Regarding IL-6, its production seems to be regulated by several signaling cascades [18,22], including by TNF-α mainly via the nuclear factor kappa-lightchain-enhancer of activated B cells (NF-κB) pathway [23,24].”
BackgroundDimerization of the cytokine receptors gp130 and LIFR analysed in single cells
Giese, B., Roderburg, C., Sommerauer, M., Wortmann, S. B., Metz, S., Heinrich, P. C., & Müller‐Newen, G. (2005) · Journal of Cell Science · doi:10.1242/jcs.02628 · Cited by 81
“Thus, one would expect that heterodimerization of gp130 with the OSMR in response to OSM or of gp130 with the IL-27R/WSX-1 in response to IL27 is ligand induced.”
BackgroundSelf-citationDUVAL, D. T., Duval, G., Kédinger, C., Poch, O., & Bœuf, H. (2003) · FEBS Letters · doi:10.1016/s0014-5793(03)01116-5 · Cited by 81
Oncostatin M inhibits myoblast differentiation and regulates muscle regeneration
Xiao, F., Wang, H., Fu, X., Li, Y., Ma, K., Sun, L., Gao, X., & Wu, Z. (2010) · Cell Research · doi:10.1038/cr.2010.144 · Cited by 80
Nutrient–gene interaction in ageing and successful ageing
Mocchegiani, E., Costarelli, L., Giacconi, R., Cipriano, C., Muti, E., Tesei, S., & Malavolta, M. (2006) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2006.01.010 · Cited by 80
Shared Cytokine Signaling Receptors: Structural Insights from the Gp130 System
Boulanger, M. J., & García, K. C. (2004) · Advances in protein chemistry · doi:10.1016/s0065-3233(04)68004-1 · Cited by 91
Jensen, B. A., Leeman‐Neill, R. J., Schlezinger, J. J., & Sherr, D. H. (2003) · Environmental Health · doi:10.1186/1476-069x-2-16 · Cited by 80
Cytokine signalling in embryonic stem cells
Kristensen, D. M., Kalisz, M., & Nielsen, J. H. (2005) · Apmis · doi:10.1111/j.1600-0463.2005.apm_391.x · Cited by 81
“The members of this cytokine family have overlapping, pleiotropic effects on a variety of different cell types and activate target genes involved in survival, apoptosis, proliferation and differentiation, as well as suppression of differentiation (12).”
BackgroundMiRNAs, epigenetics, and cancer
ROUHI, A. M., Mager, D. L., Humphries, R. K., & Kuchenbauer, F. C. (2008) · Mammalian Genome · doi:10.1007/s00335-008-9133-x · Cited by 82
“Interleukin-6 (IL-6) has been implicated in many cancer types through direct activation of several key signaling pathways (Heinrich et al. 2003) as well as indirect upregulation of DNMT1 gene expression through the transcription factor Fli-1 (Hodge et al.”
BackgroundPu, Y., Hour, T., Chuang, S., Cheng, A., Lai, M., & Kuo, M. (2004) · The Prostate · doi:10.1002/pros.20057 · Cited by 84
Luckett‐Chastain, L. R., & Gallucci, R. M. (2009) · British Journal of Dermatology · doi:10.1111/j.1365-2133.2009.09215.x · Cited by 82
IL-6 roles – Molecular pathway and clinical implication in pancreatic cancer – A systemic review
Pop, V.-V., Seicean, A., Lupan, I., Samaşcă, G., & Burz, C. C. (2016) · Immunology Letters · doi:10.1016/j.imlet.2016.11.010 · Cited by 82
Yin, L., Dai, Q., Jiang, P., Zhu, L. D., Dai, H., Yao, Z., Liu, H., Ma, X., Qu, L., & Jiang, J. (2017) · NeuroToxicology · doi:10.1016/j.neuro.2017.04.001 · Cited by 81
IL-11 facilitates a novel connection between RA joint fibroblasts and endothelial cells
Elshabrawy, H. A., Volin, M. V., Essani, A. B., et al. (2018) · Angiogenesis · doi:10.1007/s10456-017-9589-y · Cited by 80
“IL-11 belongs to the IL-6 family of cytokines comprised of leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary inhibitory factor (CNTF), cardiotropin-1 (CT-1), cardiotrophin-like related cytokine factor 1/neurotrophin-1/B-cell stimulating factor 3 (NNT-1), neuropoietin (NPN), IL-27 and IL-31 [1, 2].”
Cardiolipotoxicity, Inflammation, and Arrhythmias: Role for Interleukin-6 Molecular Mechanisms
Alì, A., Boutjdir, M., & Aromolaran, A. S. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2018.01866 · Cited by 86
Kurdi, M., & Booz, G. W. (2007) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0b013e318068dd49 · Cited by 80
Efeito do exercício no sistema imune: resposta, adaptação e sinalização celular
Terra, R., Da-Silva, S. A. G., Salerno, V. P., & Dutra, P. M. L. (2012) · Revista Brasileira de Medicina do Esporte · doi:10.1590/s1517-86922012000300015 · Cited by 84
Interleukin-6 as a Photoreceptor Neuroprotectant in an Experimental Model of Retinal Detachment
Chong, D. Y., Boehlke, C. S., Zheng, Q.-D., Zhang, L., Han, Y., & Zacks, D. N. (2008) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.07-1641 · Cited by 79
Metadata
- Authors
- HEINRICH, P. C., BEHRMANN, I., HAAN, S., HERMANNS, H. M., MÜLLER-NEWEN, G., & SCHAPER, F.
- Affiliations
- Universitätsklinikum Aachen (DE)
- Institut für Biochemie, RWTH Aachen, Universitätsklinikum, Pauwelsstrasse 30, D-52074 Aachen, Germany
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2003-08-15
- Volume
- 374
- Issue
- 1
- Pages
- 1-20
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC1223585
- OpenAlex
- W2086840459
- Cited by
- 3,272
- References
- 265
- Citations by year
- 2026: 70 · 2025: 114 · 2024: 106 · 2023: 121 · 2022: 138 · 2021: 146 · 2020: 129 · 2019: 151 · 2018: 141 · 2017: 141 · 2016: 176 · 2015: 157 · 2014: 171 · 2013: 190 · 2012: 179
- FWCI
- 50.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- 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 › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- cytokine signaling, gp130, LIF receptor, OSM receptor, JAK/STAT signaling, MAPK signaling, protein tyrosine phosphatase, suppressor of cytokine signaling, PIAS, signal termination, signal transduction, acute phase response, inflammation, rheumatoid arthritis, multiple myeloma, prostate cancer
- MeSH terms
- Animals, Humans, Infections, Models, Molecular, Phosphorylation, Protein Conformation, Wounds and Injuries, Signal Transduction, Interleukin-6, Cytokines, Protein Structure, Secondary, Receptors, Interleukin-6
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