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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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Levy, D. E., & Darnell, J. E. (2002) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm909 · Cited by 3,201
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Self-citationA family of cytokine-inducible inhibitors of signalling
Starr, R., Willson, T. A., Viney, E. M., Murray, L. J. L., Rayner, J. R., Jenkins, B. J., Gonda, T. J., Alexander, W. S., Metcalf, D., Nicola, N. A., et al. (1997) · Nature · doi:10.1038/43206 · Cited by 2,066
A new protein containing an SH2 domain that inhibits JAK kinases
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Structure and function of a new STAT-induced STAT inhibitor
Naka, T., Narazaki, M., Hirata, M., Matsumoto, T., Minamoto, S., Aono, A., Nishimoto, N., Kajita, T., Taga, T., Yoshizaki, K., et al. (1997) · Nature · doi:10.1038/43219 · Cited by 1,040
Crystal Structure of the Tyrosine Phosphatase SHP-2
Hof, P., Pluskey, S., Dhe‐Paganon, S., Eck, M. J., & Shoelson, S. E. (1998) · Cell · doi:10.1016/s0092-8674(00)80938-1 · Cited by 997
Specific Inhibition of Stat3 Signal Transduction by PIAS3
Chung, C. D., Liao, J., Liu, B., Rao, X., Jay, P., Berta, P., & Shuai, K. (1997) · Science · doi:10.1126/science.278.5344.1803 · Cited by 980
Cited by
Sorted by citations
Items 1,901–2,000 of 3,269
Eswari, S., Kumar, G. S., & Sharma, G. T. (2012) · Zygote · doi:10.1017/s0967199412000172 · Cited by 15
“LIF acts on cells by binding to the heterodimeric LIF receptor (LIFR), at the cell surface, LIFR binds with the glycoprotein gp130 (the common signaling receptor for IL-6 family cytokines) to form a high affinity receptor through which LIF signaling is triggered (Heinrich et al., 2003).”
BackgroundDissecting functions of the N-terminal domain and GAS-site recognition in STAT3 nuclear trafficking
Martincuks, A., Fahrenkamp, D., Haan, S., Herrmann, A., Küster, A., & Müller‐Newen, G. (2016) · Cellular Signalling · doi:10.1016/j.cellsig.2016.03.011 · Cited by 16
“gp130 [2] with JAK1 being the essential kinase for IL-6-dependent signaling [3].”
BackgroundSelf-citationXu, W., Meng, K., Kusano, J., et al. (2017) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.12797 · Cited by 15
Hematopoietic Cytokine Gene Duplication in Zebrafish Erythroid and Myeloid Lineages
Oltová, J., Svoboda, O., & Bartůněk, P. (2018) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2018.00174 · Cited by 15
“Supporting this, the csf1ra mutant fish (panther) have decreased numbers of microglia and macrophages (Herbomel et al., 1999; Pagan et al., 2015).”
BackgroundExposure to silver nanoparticles induces immunological dysfunction in pregnant mice
Chen, L., Wu, H., Le, L., Yang, P., Fu, F., Liu, W., & Xu, H. (2020) · Environmental Toxicology · doi:10.1002/tox.22981 · Cited by 15
“In this experiment, the increased expression of p38MAPK activated the expression of downstream genes AP-1 and MMP-9 and then upregulated the IFN-γ and IL-6 expression, which was consistent with Heinrich's research.(30) It was indicated that AgNPs could mediate inflammation through the p38MAPK-AP-1-MMP-9 signaling path…”
ResultWound Induced Hair Neogenesis – A Novel Paradigm for Studying Regeneration and Aging
Bhoopalam, M., Garza, L. A., & Reddy, S. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.582346 · Cited by 15
Adipocyte Oncostatin Receptor Regulates Adipose Tissue Homeostasis and Inflammation
Sánchez‐Infantes, D., & Stephens, J. M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.612013 · Cited by 15
“These cytokines regulate a variety of complex biological processes, including hematopoiesis, immune responses, inflammation, stem cell potency, mammalian reproduction, cardiovascular action, and neuronal survival (15).”
BackgroundWang, H., Si, S., Jiang, M., Chen, L., Huang, K., & Yu, W. (2021) · Oncology Letters · doi:10.3892/ol.2021.12924 · Cited by 16
Preshaw, P. M., & Taylor, J. J. (2012) · Elsevier eBooks · doi:10.1016/b978-1-4377-0416-7.00021-4 · Cited by 15
Oncostatin M-induced genes in human astrocytomas
Krona, A., Åman, P., Örndal, C., et al. (2007) · International Journal of Oncology · doi:10.3892/ijo.31.6.1457 · Cited by 15
Babilas, P., Fiebig, B. S., Aslanidis, C., et al. (2009) · British Journal of Dermatology · doi:10.1111/j.1365-2133.2009.09237.x · Cited by 15
Szigyarto, C. A., Sibbons, P. D., Williams, G., et al. (2009) · Journal of Histochemistry & Cytochemistry · doi:10.1369/jhc.2009.954420 · Cited by 15
Gibson, R. M., Laszlo, G. S., & Nathanson, N. M. (2005) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2005.05.014 · Cited by 15
“LIF-stimulated dimerization of LIFR and gp130 results in activation of the Jak/Tyk family of non-receptor protein tyrosine kinases ([6], and references therein).”
BackgroundSoluble mediators in plasma from irritable bowel syndrome patients excite rat submucosal neurons
O’Malley, D., Buckley, M. M., McKernan, D. P., Quigley, E. M. M., Cryan, J. F., & Dinan, T. G. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2014.08.005 · Cited by 15
“We did observe that IBS plasma activates the ERK/MAPK cascade, which is associated with transcription, cell survival, differentiation and proliferation (Heinrich et al., 2003) but is also important in mediating the effects of other neuromodulators (O’Malley and Harvey, 2004).”
BackgroundFollicular Immunology Environment and the Influence on In Vitro Fertilization Outcome
Vujisić, S., & Lepej, S. Ž. (2005) · Current Women s Health Reviews · doi:10.2174/1573404052950258 · Cited by 16
“The variability of results in IL-1 detection by using EIAs from different manufacturers has been previously recognized and could, at least in part, explain the conflicting data [25].”
BackgroundUnbiased identification of substrates for the Epac1-inducible E3 ubiquitin ligase component SOCS-3
Williams, J. J. L., & Palmer, T. M. (2012) · Biochemical Society Transactions · doi:10.1042/bst20110629 · Cited by 15
LPS hypersensitivity of gp130 mutant mice is independent of elevated haemopoietic TLR4 signaling
Greenhill, C., Gould, J. A., Ernst, M., Jarnicki, A., Hertzog, P. J., Mansell, A. S., & Jenkins, B. J. (2011) · Immunology and Cell Biology · doi:10.1038/icb.2011.56 · Cited by 15
Lv, L., Zhang, J., Huang, X., et al. (2008) · Archives of Medical Research · doi:10.1016/j.arcmed.2008.06.001 · Cited by 15
“SOCS-3 is one of eight members of the SOCS signaling family (28) and was discovered for its ability to inhibit tyrosine phosphorylation of STAT3 through binding to gp130 and JAKs (29).”
BackgroundInterleukin-6 Attenuates Serotonin 2A Receptor Signaling by Activating the JAK-STAT Pathway
Donegan, J. J., Patton, M. S., Chavera, T. S., Berg, K. A., Morilak, D. A., & Girotti, M. (2014) · Molecular Pharmacology · doi:10.1124/mol.114.096289 · Cited by 16
“Thus, understanding the functional regulation of this receptor could have important implications for improved treatment of schizophrenia and other psychiatric disorders.”
BackgroundSerum Cytokine Profiles in Children with Crohn’s Disease
Vasilyeva, E. M., Abdulkhakov, S. R., Черепнев, Г. В., et al. (2016) · Mediators of Inflammation · doi:10.1155/2016/7420127 · Cited by 15
“IL-6 is a B cell differentiating factor [52] that, when combined with TGFβ, promotes the differentiation ofTh17 lymphocytes [53].”
BackgroundOkuda, M., Inoue, J., Fujiwara, N., Kawano, T., & Inazawa, J. (2017) · Oncotarget · doi:10.18632/oncotarget.16668 · Cited by 15
“IL-6 is a cytokine that triggers the downstream activation of STAT3 transcription factors [20].”
BackgroundLiu, Y., Song, F., Wu, S., et al. (2017) · American Journal of Orthodontics and Dentofacial Orthopedics · doi:10.1016/j.ajodo.2017.03.026 · Cited by 15
“Glycoprotein 130 (gp130) is the central player of the receptor complex formed by IL-6–type cytokines during the activation of the IL-6 signaling pathway, which is composed of 918 amino acids with a single transmembrane domain.(19,20) Gp130 itself does not seem to have tyrosine kinase activity and cannot bind directly…”
BackgroundMesenchymal stem cells targeting PI3K/AKT pathway in leukemic model
Ahmed, E. S. A., Ahmed, N. H., Medhat, A. M., Said, U. Z., Rashed, L. A., & Rahman, A. (2019) · Tumor Biology · doi:10.1177/1010428319846803 · Cited by 14
Canesin, G., Krzyzanowska, A., Hellsten, R., & Bjartell, A. S. (2020) · Current Opinion in Endocrine and Metabolic Research · doi:10.1016/j.coemr.2020.02.004 · Cited by 16
Coulouarn, C., Lefebvre, G. C., Daveau, R., Letellier, F., Hiron, M., Drouot, L., Daveau, M., & Salier, J. (2005) · Hepatology · doi:10.1002/hep.20848 · Cited by 19
“The major proinflammatory cytokine-regulated pathways and relevant transcription factors are summarized: (1) the IL-1 /NF- B pathway, (2) the IL-1 /MAP kinase/AP-1 and C/EBP pathway, and (3) the IL-6/STAT3 pathway.”
BackgroundInfluentialInterleukin-6 regulation of direct lung ischemia reperfusion injury
Farivar, A. S., Merry, H. E., Fica-Delgado, M. J., McCourtie, A. S., Mackinnon-Patterson, B. C., & Mulligan, M. S. (2006) · The Annals of Thoracic Surgery · doi:10.1016/j.athoracsur.2006.03.060 · Cited by 15
Bogner, V., Kirchhoff, C., Baker, H. V., et al. (2007) · Langenbeck s Archives of Surgery · doi:10.1007/s00423-007-0182-5 · Cited by 15
“These factors are well known representatives of post-injury acute-phase proteins [17].”
BackgroundCaspase-mediated cleavage of the signal-transducing IL-6 receptor subunit gp130
Graf, D., Haselow, K., Münks, I., Bode, J. G., & Häussinger, D. (2008) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2008.06.009 · Cited by 14
Johnson, R. L., Huang, R., Jadhav, A., et al. (2009) · Molecular BioSystems · doi:10.1039/b902021g · Cited by 15
Rinis, N., Küster, A., de Leur, H. S.-V., Mohr, A., & Müller‐Newen, G. (2014) · Cell Communication and Signaling · doi:10.1186/1478-811x-12-14 · Cited by 15
“The MAPK cascade gets initiated by recruitment and activation of the SH2-domaincontaining tyrosine phosphatase 2 (SHP2) (reviewed in [2]).”
BackgroundSelf-citationSafhi, M. M. A., Rutherford, C. L., Ledent, C. A., Sands, W. A., & Palmer, T. M. (2010) · Molecular Pharmacology · doi:10.1124/mol.109.062455 · Cited by 15
“the protein tyrosine phosphatase SHP-2 via their SH2 domains (Heinrich et al., 2003).”
BackgroundLloyd, P. G., Sheehy, A. J., Edwards, J. M., et al. (2008) · Coronary Artery Disease · doi:10.1097/mca.0b013e3282f9d3be · Cited by 15
Pachernı́k, J., Horváth, V., Kubala, L., Dvořák, P., Kozubı́k, A., & Hampl, A. (2007) · Folia Biologica · doi:10.14712/fb2007053050157 · Cited by 15
“Another major signalling pathway downstream of LIFR/gp130 is the mitogen-activated protein kinase (MAPK) cascade, here in particular the Ras -> ERK cascade (Seiler et al., 2001; Heinrich et al., 2003).”
BackgroundXu, C., Chen, W., Nie, X., Xu, R., Feng, X., Chen, Z., & Wang, D. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1654622 · Cited by 21
“The IL-6 signaling pathway involves gp130, which recruits co-receptors like the leukemia inhibitory factor (LIF) receptor and oncostatin M (OSM) receptor, activating JAK/STAT and MAPK cascades (70).”
Ma, X., Tian, D., Lv, W., Gao, B., Ma, Z., & Zheng, X. (2021) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2021.10396 · Cited by 14
Sreenivasan, L., Li, L. V., Leclair, P., & Lim, C. J. (2022) · Cells · doi:10.3390/cells11030381 · Cited by 16
Ponasenko, A. V., Sinitsky, M. Y., Minina, V. I., Vesnina, A. D., Khutornaya, M. V., Prosekov, A. Y., & Барбараш, О. Л. (2022) · Journal of Personalized Medicine · doi:10.3390/jpm12020238 · Cited by 14
“The results herein describing an increased risk of obesity in middle-aged males carrying the C/T genotype of the IL6R gene (rs2229238) are consistent with the findings of an association between the C/T genotype of this gene and an increased risk of obesity in schoolboys from Taiwan [31].”
BackgroundInfluentialInflammation targeted nanomedicines: Patents and applications in cancer therapy
Krishnamurthy, P. T., Gangadharappa, H. V., Lila, A. S. A., Moin, A., Mehmood, K., Krishna, K. L., Hussain, T., Alafnan, A., Shakil, S., & Rizvi, S. M. D. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.04.004 · Cited by 13
Cytokines and Production of Aberrantly O -Glycosylated IgA1, the Main Autoantigen in IgA Nephropathy
Person, T., King, R. G., Rizk, D. V., Novák, J., Green, T. J., & Reily, C. (2022) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2022.0039 · Cited by 15
Schumacher, N., Thomsen, I., Brundert, F., Hejret, V., Düsterhöft, S., Tichý, B., Schmidt‐Arras, D., Voß, M., & Rose‐John, S. (2023) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2023.119489 · Cited by 14
Pavlova, E., Лепеха, Л. Н., Rybalkina, E. Y., Вячеславович, Т. Р., Sychevskaya, K. A., Voronezhskaya, E. E., Masyutin, A. G., Эргешов, А. Э., & Erokhina, M. V. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241914839 · Cited by 14
“IL-6 signaling primarily occurs through JAK/STAT pathway, predominantly via STAT3 [77].”
BackgroundImbalanced gp130 signalling in ApoE-deficient mice protects against atherosclerosis
Jones, G. W., McLeod, L., Kennedy, C. L., Bozinovski, S., Najdovska, M., & Jenkins, B. J. (2014) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2014.12.037 · Cited by 17
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“These cytokines all promote cellular responses through the same signal-transducing subunit (gp130) [11], which makes them functionally redundant [13].”
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Branco, R. C. S., Camargo, R. L., Batista, T. M., Vettorazzi, J. F., Borck, P. C., Santos‐Silva, J. C. R., Boschero, A. C., Zoppi, C. C., & Carneiro, E. M. (2017) · The FASEB Journal · doi:10.1096/fj.201600326rrr · Cited by 14
Functional interleukin‐6 receptor‐α is located in tanycytes at the base of the third ventricle
Anesten, F., dos Santos, C. P., Gidestrand, E., Schéle, E., Pálsdóttir, V., Swedung‐Wettervik, T., Meister, B., Skibicka, K. P., & Jansson, J. (2017) · Journal of Neuroendocrinology · doi:10.1111/jne.12546 · Cited by 14
Neurotrophic Factors and Their Receptors Are Altered by the Mere Partial IGF-1 Deficiency
Castilla‐Cortázar, I., Iturrieta-Zuazo, I., García‐Magariño, M., Puche, J. E., Martín‐Estal, I., Aguirre, G. A., Femat‐Roldán, G., Cantú-Martínez, L., & Muñoz, Ú. (2019) · Neuroscience · doi:10.1016/j.neuroscience.2019.01.041 · Cited by 14
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LIF and bFGF enhanced chicken primordial follicle activation by Wnt/β-catenin pathway
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TNF-&agr;-Mediated Stress-Induced Early Pregnancy Loss:A Possible Role of Leukemia Inhibitory Factor
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“IL6 binds to IL6R and this complex activates an intracellular signalling cascade that leads to the inflammatory response.(16) Chronic inflammation contributes to the progression of CKD by increases in the release of cytokine and in the production and activity of adhesion molecules.”
Tiwari, P., Tripathi, L. P., Nishikawa-Matsumura, T., Ahmad, S., Song, S.-N. J., Isobe, T., Mizuguchi, K., & Yoshizaki, K. (2013) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2013.01.024 · Cited by 14
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Glucagon counteracts interleukin-6 dependent gene expression by redundant action of Epac and PKA
Khouri, C., Dittrich, A., Sackett, S. D., Denecke, B., Trautwein, C., & Schaper, F. (2011) · Biological Chemistry · doi:10.1515/bc.2011.171 · Cited by 15
Self-citationIL-6 and PPARgamma signalling in human PC-3 prostate cancer cells.
Pitulis, N., Papageorgiou, E. G., Τέντα, Ρ., Lembessis, P., & Koutsilieris, M. (2009) · PubMed · Cited by 14
A receptor fusion protein for the inhibition of murine oncostatin M
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“Gp130 is the common receptor subunit of the IL-6 family of cytokines comprising IL-6, OSM, LIF, IL-11, IL-27, ciliary neurotrophic factor, cardiotrophin-1, cardiotrophin-like cytokine and neuropoetin [23].”
BackgroundSelf-citationNovel control of cAMP-regulated transcription in vascular endothelial cells
Milne, G. R., Palmer, T. M., & Yarwood, S. J. (2012) · Biochemical Society Transactions · doi:10.1042/bst20110606 · Cited by 13
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“Therefore, OMSR activates JAK/ STAT and MAPK pathways and stimulates the production of a variety of cytokines and inflammatory substances [4,6,20].”
BackgroundCytokines of the Immune System
Dembić, Z. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-419998-9.00005-5 · Cited by 14
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“It was predominantly expressed in the cells of hematopoietic system and regulated cell development and activation (Kawamura et al., 1994;Musso et al., 1995;Heinrich et al., 2003).”
BackgroundBiliary tract cancer stem cells - translational options and challenges
Mayr, C., Ocker, M., Ritter, M., Pichler, M., Neureiter, D., & Kiesslich, T. (2017) · World Journal of Gastroenterology · doi:10.3748/wjg.v23.i14.2470 · Cited by 14
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“Lines of evidence showed that negative regulating proteins played an essential role in homeostasis, such as suppressors of SOCS proteins as counterparts for STAT (4, 5), Mdm2 as negative regulator for p53 (6–8), and CTLA4 as a brake for TCR-mediated T cell activation (9–11).”
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Krabbe, J., Ruske, N., Braunschweig, T. A., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-23513-0 · Cited by 14
Transcriptome analysis of BmN cells following over-expression of BmSTAT
Hu, X., Zhang, X., Wang, J., et al. (2015) · Molecular Genetics and Genomics · doi:10.1007/s00438-015-1065-z · Cited by 14
“Indeed, MAPK signaling (Rane and Reddy 2000; Shuai 2000; Heinrich et al. 2003), PI3K signaling (Foster et al.”
Kim, Y. S., Kim, G. R., Park, M., et al. (2019) · Tissue Engineering and Regenerative Medicine · doi:10.1007/s13770-019-00225-8 · Cited by 14
Gene expression profile analysis of the rabbit retinal vein occlusion model
Neo, T., Gozawa, M., Takamura, Y., Inatani, M., & Oki, M. (2020) · PLoS ONE · doi:10.1371/journal.pone.0236928 · Cited by 15
Cytokines and Chemokines inMycobacterium tuberculosisInfection
Domingo-Gonzalez, R., Prince, O. A., Cooper, A. M., & Khader, S. A. (2017) · ASM Press eBooks · doi:10.1128/9781555819569.ch2 · Cited by 15
Neurotrophic Factors and Their Receptors
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Development of an IL-6 Inhibitor Based on the Functional Analysis of Murine IL-6Rα1
Wiesinger, M., Haan, S., Wüller, S., Kauffmann, M.-E., Recker, T., Küster, A., Heinrich, P. C., & Müller‐Newen, G. (2009) · Chemistry & Biology · doi:10.1016/j.chembiol.2009.06.010 · Cited by 16
“Gp130 mediates activation of the Jak/STAT signaling pathway (Heinrich et al., 2003), which leads to the expression of well defined STAT3 target genes including the acute phase proteins, Bcl-2, and VEGF (Sepulveda et al.”
BackgroundSelf-citationLi, Y., Chang, J. W. C., Hsieh, L., & Yeh, K. (2010) · Cellular Immunology · doi:10.1016/j.cellimm.2010.07.014 · Cited by 14
Hagiwara, S., Iwasaka, H., & Noguchi, T. (2007) · Journal of Anesthesia · doi:10.1007/s00540-006-0468-8 · Cited by 14
“IL-6 is a hematopoietin cytokine that exerts pleiotropic effects and plays a crucial role in survival, acute phase protein production, fever, inflammation, and cell migration [27].”
BackgroundRetractedInterleukin-6 expands homeostatic space for peripheral T cells
Hong, C., Nam, A. S., Keller, H. R., Ligons, D. L., Park, J., Yoon, H., Park, J. J., Luckey, M. A., & Park, J.-H. (2013) · Cytokine · doi:10.1016/j.cyto.2013.08.001 · Cited by 14
Woodchuck interleukin-6 gene: structure, characterization, and biologic activity
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“Upon phosphorylation, STAT3 translocates into the nucleus ultimately leading to the expression of target genes involved in differentiation, survival, apoptosis and proliferation (reviewed in [28]).”
BackgroundKawazoe, S., Ikeda, N., Miki, K., Shibuya, M., Morikawa, K., Nakano, S., Oshimura, M., Hisatome, I., & Shirayoshi, Y. (2009) · Development Growth & Differentiation · doi:10.1111/j.1440-169x.2008.01082.x · Cited by 14
“Signal transduction involves the activation of Janus kinase (JAK) tyrosine kinase family members, leading to the activation of STAT3 (Heinrich et al. 2003).”
BackgroundVesely, D. L., Hoffman‐Liebermann, B., & Liebermann, D. A. (2006) · Oncogene · doi:10.1038/sj.onc.1210109 · Cited by 14
“Next we asked whether IL-6 treatment of M1-t-p53 results in phosphorylation-dependent activation of Akt, and if so, whether inhibition of the PI3K/Akt pathway with its specific inhibitor LY294002, (Vlahos et al., 1994; Yano et al., 1995; Hu et al., 2000; Heinrich et al., 2003), would abrogate IL-6 protection.”
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Westra, J., Bijzet, J., der Meer, B. D.-V., et al. (2005) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2005.043232 · Cited by 14
Nystuen, A., Gonzalez-Lopez, E., Kauper, K. A., Eade, K., & Aaberg, T. M. (2025) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2025.06.005 · Cited by 11
Iaquinta, M. R., Martini, F., D’Agostino, A., Trevisiol, L., Bersani, M., Torreggiani, E., Tognon, M. G., Rotondo, J. C., & Mazzoni, E. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.873814 · Cited by 13
“Members of this family have both pro- and anti-inflammatory qualities, and they play important roles in hematopoiesis, as well as acute-phase and immunological responses in the organism (Heinrich et al., 2003).”
BackgroundThe tendency of anemia of inflammation in periodontal diseases
Han, Y., Luo, Z., Yue, Z., Li, M., Xv, M., Chang, S. H., Zhan, Y., & Hou, J. (2023) · Clinical Science · doi:10.1042/cs20220524 · Cited by 14
Oncostatin M Reduces Pathological Neovascularization in the Retina Through Müller Cell Activation
Rapp, J., Hospach, A., Liang, P., Schwämmle, M. E., Renz, L. M., Agostini, H. T., Schlunck, G., & Bucher, F. (2024) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.65.1.22 · Cited by 13
“12 In our previous work, we reported a strong angiomodulatory effect of CNTF-induced STAT3 signaling in various mouse models of vasoproliferative eye diseases which was based on a direct anti-angiogenic effect on vascular endothelial cells as well as an indirect, Müller cell–mediated effect.”
Unraveling the role of STAT3 in Cancer Cachexia: pathogenic mechanisms and therapeutic opportunities
Lv, X., & Ding, S. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1608612 · Cited by 17
Parodi, A., Sanguineti, R., Catalano, M., et al. (2009) · Toxicology Letters · doi:10.1016/j.toxlet.2009.10.013 · Cited by 13
Oncostatin M Modulation of Lipid Storage
Elks, C. M., & Stephens, J. M. (2015) · Biology · doi:10.3390/biology4010151 · Cited by 13
“survival (reviewed in [2]).”
Thacker, J. D., Brown, M. A., Rest, R. F., et al. (2009) · Journal of Natural Products · doi:10.1021/np900360m · Cited by 13
Chu, N., Lin, F.-H., Chin, H.-C., & Hong, Y.-J. (2011) · Lipids in Health and Disease · doi:10.1186/1476-511x-10-136 · Cited by 13
GT-repeat extension in the IL11 promoter is associated with Hirschsprung's disease (HSCR)
Haase, M., Schulze, A., Grover, S., et al. (2018) · Gene · doi:10.1016/j.gene.2018.07.054 · Cited by 13
Deciphering Master Gene Regulators and Associated Networks of Human Mesenchymal Stromal Cells
Sánchez-Luis, E., Garcia, A. J., Campos-Laborie, F. J., Sanchez-Guijo, F. M., & Rivas, J. D. L. (2020) · Biomolecules · doi:10.3390/biom10040557 · Cited by 13
“Moreover, other genes in this cluster are EGFR2 and GREM1, which are genes necessary for the skeletal development and bone homeostasis and are also activated during bone cells response to mechanical strain [26,27].”
BackgroundShabestari, M. G., Shabestari, Y. R., Landin, M. A., Pepaj, M., Cleland, T. P., Reseland, J. E., & Eriksen, E. F. (2020) · International Journal of Rheumatic Diseases · doi:10.1111/1756-185x.13843 · Cited by 13
Witkowski, S. M., de Castro, E. M., Nagashima, S., Martins, A. P. C., Okamoto, C. T., Nakata, G. T. M., Collete, M., Souza, C. M., & de Noronha, L. (2020) · Cytokine · doi:10.1016/j.cyto.2020.155118 · Cited by 13
Regulation of S100As Expression by Inflammatory Cytokines in Chronic Lymphocytic Leukemia
Ajtić, O. M., Subotički, T., Diklić, M., Đikić, D., Vukotić, M., Dragojević, T., Živković, E., Antic, D. A., & Čokić, V. P. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23136952 · Cited by 13
“IL-6 and JAK2/STAT3 act as feedback that stimulates the process of tumorigenesis and metastasis in some types of malignancies [20].”
BackgroundRegulatory Mechanisms Controlling Inflammation and Synthesis of Acute Phase Proteins
Jura, J., & Koj, A. (2011) · InTech eBooks · doi:10.5772/18207 · Cited by 13
“In subsequent years it was found that IL-6 is the most important member of a large cytokine family sharing common receptor subunit gp130 and showing a high degree of redundancy (Sehgal et al., 1995; Heinrich et al., 2003; Baumann, 2003).”
BackgroundAschenbach, L. C., Hester, K. E., McCann, N. C., Zhang, J., Dimitriadis, E., & Duffy, D. M. (2012) · Contraception · doi:10.1016/j.contraception.2012.09.032 · Cited by 13
“LIF actions are mediated by the LIF receptor complex, a heterodimer of the LIF receptor and gp130, a common coreceptor for the interleukin-6 (IL-6) cytokine family [11].”
BackgroundOka, M., Sumita, N., Sakaguchi, M., Iwasaki, T., Bito, T., Kageshita, T., Sato, K., Fukami, Y., & Nishigori, C. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.001073 · Cited by 13
Park, K. W., Lin, C., Li, K., & Lee, Y. (2015) · PLoS ONE · doi:10.1371/journal.pone.0138301 · Cited by 14
“Binding of IL-6 to gp130 receptor induces SOCS3 expression as a transcription target gene of the STAT3 signaling pathway [29].”
BackgroundLee, S. G., Lee, C. G., Wu, H., Oh, C. S., Chung, S. W., & Kim, S. G. (2015) · Scientific Reports · doi:10.1038/srep15643 · Cited by 13
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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