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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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Self-citationA family of cytokine-inducible inhibitors of signalling
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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
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Crystal Structure of the Tyrosine Phosphatase SHP-2
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Specific Inhibition of Stat3 Signal Transduction by PIAS3
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Cited by
Sorted by citations
Items 401–500 of 3,269
Small-molecule inhibition of STAT3 in radioresistant head and neck squamous cell carcinoma
Bharadwaj, U., Eckols, T. K., Xu, X., Kasembeli, M. M., Chen, Y., Adachi, M., Song, Y., Mo, Q., Lai, S. Y., & Tweardy, D. J. (2016) · Oncotarget · doi:10.18632/oncotarget.8368 · Cited by 115
“the family of IL-6 cytokine receptors or G-protein coupled receptors, GPCR) [11, 12], and Src kinases (e.”
BackgroundThe effect of exercise on IL‐6‐induced cachexia in the ApcMin/+ mouse
Puppa, M., White, J. P., Velázquez, K. T., Baltgalvis, K. A., Sato, S., Baynes, J., & Carson, J. A. (2011) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1007/s13539-011-0047-1 · Cited by 120
“properties as well as the ability to activate transcription of genes involved in cell proliferation, differentiation, and apoptosis [35].”
BackgroundToriseva, M., Laato, M. K., Carpén, O., Ruohonen, S. T., Savontaus, E., Inada, M., Krane, S. M., & Kähäri, V. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042596 · Cited by 117
“It is of note that Il6 which codes for proinflammatory cytokine IL-6, an important regulator of the acute-phase response to injury and infection [39], was downregulated in Mmp13 tissues at both 7 d and 14 d (FC,1 and FC,1.”
BackgroundMany good reasons to have STAT3 in the heart
Hilfiker-Kleiner, D., Hilfiker, A., & Drexler, H. (2005) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2005.02.003 · Cited by 115
The role of interleukin-6 in glucose homeostasis and lipid metabolism
Lehrskov, L. L., & Christensen, R. H. (2019) · Seminars in Immunopathology · doi:10.1007/s00281-019-00747-2 · Cited by 114
Terrell, A. M., Crisostomo, P. R., Wairiuko, G. M., Wang, M., Morrell, E. D., & Meldrum, D. R. (2006) · Shock · doi:10.1097/01.shk.0000226341.32786.b9 · Cited by 118
“STATs 1 and 3 are known to bind to the gp130 receptor (99, 100), with STAT3 being more potently activated than STAT1 (96, 101).”
BackgroundInfluentialInflammatory Mediators in Gestational Diabetes Mellitus
Richardson, A. C., & Carpenter, M. W. (2007) · Obstetrics and Gynecology Clinics of North America · doi:10.1016/j.ogc.2007.04.001 · Cited by 117
Characterization and Regulation of Mechanical Loading‐Induced Compensatory Muscle Hypertrophy
Adams, G. R., & Bamman, M. M. (2012) · Comprehensive physiology · doi:10.1002/cphy.c110066 · Cited by 123
Regulation of CCL20 expression in astrocytes by IL‐6 and IL‐17
Meares, G. P., Ma, X., Qin, H., & Benveniste, E. N. (2012) · Glia · doi:10.1002/glia.22307 · Cited by 117
“IL-6 signals by binding to the IL-6 receptor (IL-6R) and glycoprotein 130 (gp130) leading to activation of the JAK/STAT3 and MAPK pathways (Heinrich et al., 2003).”
BackgroundUeki, Y., Wang, J., Chollangi, S., & Ash, J. D. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.05180.x · Cited by 113
Mimetics of Caloric Restriction Include Agonists of Lipid-activated Nuclear Receptors
Corton, J. C., Apte, U. M., Anderson, S. P., Limaye, P. B., Yoon, L., Latendresse, J. R., Dunn, C. S., Everitt, J. I., Voss, K. A., Swanson, C. L., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m406739200 · Cited by 114
Li, J. (2013) · JAK-STAT · doi:10.4161/jkst.23930 · Cited by 112
“They are pleiotropic cytokines, sharing the glycoprotein chain gp130 as a common signal transducer.(13,15,16) The binding of IL-6 family cytokines to their receptors induces the homodimerization of gp130 and subsequently activates the gp130-associated JAKs.”
BackgroundYu, D., Ye, T., Xiang, Y., Shi, Z., Zhang, J., Lou, B., Zhang, F., Chen, B., & Zhou, M. (2017) · OncoTargets and Therapy · doi:10.2147/ott.s136840 · Cited by 112
“20 IL-6 is one of the most important traditional activators of STAT3.”
Metcalfe, R. D., Putoczki, T. L., & Griffin, M. D. W. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01424 · Cited by 116
“SHP2 is also recruited by gp130 at the intracellular domain (133), interacting with Tyr759 providing the link between gp130 and the MAPK pathway (134).”
BackgroundMethodIL-6 Plays a Unique Role in Initiating c-Maf Expression during Early Stage of CD4 T Cell Activation
Yang, Y., Ochando, J., Yopp, A. C., Bromberg, J. S., & Ding, Y. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.5.2720 · Cited by 112
“Stat3 is recruited to gp130 through its Src homology protein 2 (SHP2) domain, and initiates the JAK-STAT signaling pathway.”
BackgroundInfluentialRapid effects of 17β-estradiol on cell signaling and function of Mytilus hemocytes
Canesi, L., Ciacci, C., Betti, M., Lorusso, L. C., Marchi, B., Burattini, S., Falcieri, E., & Gallo, G. (2004) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2003.12.003 · Cited by 112
c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling
Peruzzi, B., Cappariello, A., Fattore, A. D., Rucci, N., de Benedetti, F., & Teti, A. (2012) · Nature Communications · doi:10.1038/ncomms1651 · Cited by 112
“They activate target genes involved in differentiation, survival, apoptosis and proliferation in several cell type”
BackgroundEhlting, C., Lai, W. S., Schaper, F., Brenndörfer, E. D., Matthes, R.-J., Heinrich, P. C., Ludwig, S., Blackshear, P. J., Gaestel, M., Häussinger, D., et al. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.5.2813 · Cited by 111
“A fter its discovery, the signaling cascade mediated by the activation of members of the tyrosine kinase family Jak and the subsequent activation of STAT factors has been recognized as one of the key events in the signal transduction of many different stimuli such as ILs, IFNs, or growth factors (1, 2).”
BackgroundSelf-citationSantoni‐Rugiu, E., Jelnes, P., Thorgeirsson, S. S., & Bisgaard, H. C. (2005) · Apmis · doi:10.1111/j.1600-0463.2005.apm_386.x · Cited by 114
“In addition, OSM is able to signal through LIFR/gp130, reflecting a certain capacity of these cytokines to share and interchange the use of their receptors (124, 125).”
BackgroundStructural Organization of a Full-Length gp130/LIF-R Cytokine Receptor Transmembrane Complex
Skiniotis, G., Lupardus, P. J., Martick, M. M., Walz, T., & García, K. C. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.08.011 · Cited by 112
“(Heinrich et al., 2003).”
BackgroundChen, Q., Wang, W., Bruce, R., Li, H., Schleider, D. M., Mulbury, M. J., Bain, M. D., Wallace, P. K., Baumann, H., & Evans, S. S. (2004) · Immunity · doi:10.1016/s1074-7613(03)00358-3 · Cited by 110
Nerve Growth Factor in Rheumatic Diseases
Seidel, M. F., Albarran, M. H., Forkert, R., & Otten, U. (2009) · Seminars in Arthritis and Rheumatism · doi:10.1016/j.semarthrit.2009.03.002 · Cited by 111
“Structurally less elated cytokines include the neuropoietic cytokine famly consisting of IL-6 family members, including IL-6, iliary neurotrophic factor (CNTF) (19), leukemia inhibtory factor/cholinergic differentiation factor (20), IL-11, ucostatin M, or cardiotropin-1 (21).”
BackgroundNeuroimmune regulation of homeostatic synaptic plasticity
Pribiag, H., & Stellwagen, D. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.06.008 · Cited by 106
Hoene, M., Runge, H., Häring, H. U., Schleicher, E. D., & Weigert, C. (2013) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00025.2012 · Cited by 110
Cai, T., Zhang, Y., Ho, Y.-L. A., Link, N., Sun, J., Huang, J., Cai, T. A., Damrauer, S. M., Ahuja, Y., Honerlaw, J. P., et al. (2018) · JAMA Cardiology · doi:10.1001/jamacardio.2018.2287 · Cited by 114
Interleukin‐6 is a direct mediator of T cell migration
Weißenbach, M., Clahsen, T., Weber, C., Spitzer, D., Wirth, D., Vestweber, D., Heinrich, P. C., & Schaper, F. (2004) · European Journal of Immunology · doi:10.1002/eji.200425237 · Cited by 112
Self-citationPark, J. Y., Gao, W., Whiston, R., Strom, T. B., Metcalfe, S. M., & Fahmy, T. M. (2010) · Molecular Pharmaceutics · doi:10.1021/mp100203a · Cited by 109
West, N. R., Murray, J. I., & Watson, P. H. (2013) · Oncogene · doi:10.1038/onc.2013.105 · Cited by 114
Genome-wide search for sarcoidosis susceptibility genes in African Americans
Iannuzzi, M. C., Iyengar, S. K., Gray‐McGuire, C., Elston, R. C., Baughman, R. P., Donohue, J. F., Hirst, K., Judson, M. A., Kavuru, M. S., MALIARIK, M. J., et al. (2005) · Genes and Immunity · doi:10.1038/sj.gene.6364235 · Cited by 109
Malignancies in systemic lupus erythematosus
Goobie, G. C., Bernatsky, S., Ramsey‐Goldman, R., & Clarke, A. E. (2015) · Current Opinion in Rheumatology · doi:10.1097/bor.0000000000000202 · Cited by 111
“Interleukin-6 is a cytokine released from monocytes and macrophages during inflammatory states that leads to increased growth and differentiation with decreased apoptosis in neutrophils, monocytes, and T and B cells [18].”
BackgroundProinflammatory Cytokines and Skin Wound Healing in Mice
Nosenko, M. A., Ambaryan, S. G., & Drutskaya, M. S. (2019) · Molecular Biology · doi:10.1134/s0026893319050121 · Cited by 110
Chattopadhyay, S., Tracy, E., Liang, P., Robledo, O., Rose‐John, S., & Baumann, H. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m609655200 · Cited by 108
Sikorski, K., Czerwoniec, A., Bujnicki, J. M., Wesoły, J., & Bluyssen, H. A. R. (2011) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2011.06.003 · Cited by 110
“and STAT3 in different cell types [65,66].”
Dai, X., Ahn, K. S., Kim, C., Siveen, K. S., Ong, T. H., Shanmugam, M. K., Li, F., Shi, J., Kumar, A. P., Wang, L. Z., et al. (2015) · Molecular Oncology · doi:10.1016/j.molonc.2014.12.008 · Cited by 107
“…kinases such as JAK1 and JAK2, but it also can be activated by othermechanism(s), including reversible acetylation and non-receptor tyrosine kinases such as Src which is upstream of STAT3 and commonly overexpressed in a variety of solid tumor cells (Heinrich et al., 2003; Levy and Darnell, 2002).”
BackgroundGleitz, H. F. E., Dugourd, A. J. F., Leimkühler, N. B., Snoeren, I., Fuchs, S. N. R., Menzel, S., Ziegler, S. M., Kröger, N. M., Triviai, I., Büsche, G., et al. (2020) · Blood · doi:10.1182/blood.2019004095 · Cited by 108
Leukemia inhibitory factor and interleukin-11: Critical regulators in the establishment of pregnancy
Paiva, P., Menkhorst, E. M., Salamonsen, L. A., & Dimitriadis, E. (2009) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2009.07.001 · Cited by 107
“Signal transduction is attenuated via the suppressors of cytokine signaling (SOCS) family of cytoplasmic proteins or protein inhibitor of activated STAT (PIAS) proteins [12,13] that complete a negative feedback loop [5].”
BackgroundAnalytic Review: Interleukin-6 in Surgery, Trauma, and Critical Care: Part I: Basic Science
Jawa, R. S., Anillo, S., Huntoon, K. M., Baumann, H., & Kulaylat, M. N. (2011) · Journal of Intensive Care Medicine · doi:10.1177/0885066610395678 · Cited by 112
Nerstedt, A., Johansson, A., Andersson, C. X., Cansby, E., Smith, U., & Mahlapuu, M. (2010) · Diabetologia · doi:10.1007/s00125-010-1856-z · Cited by 106
Multifaceted Roles of Interleukin-6 in Adipocyte–Breast Cancer Cell Interaction
Gyamfi, J., Eom, M., Koo, J. S., & Choi, J. (2018) · Translational Oncology · doi:10.1016/j.tranon.2017.12.009 · Cited by 109
Mechanisms involved in IL-6-induced muscular mechanical hyperalgesia in mice
Manjavachi, M. N., Motta, E. M., Marotta, D. M., Leite, D. F. P., & Calixto, J. Β. (2010) · Pain · doi:10.1016/j.pain.2010.07.018 · Cited by 106
“Earlier studies showed that IL-6 is able to activate p38 MAPK, ERK and JNK in different cell types [14].”
BackgroundFat in flames: influence of cytokines and pattern recognition receptors on adipocyte lipolysis
Grant, R. W., & Stephens, J. M. (2015) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00053.2015 · Cited by 109
Stat3 Phosphorylation Mediates Resistance of Primary Human T Cells to Regulatory T Cell Suppression
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“IL-6 signals through a heterodimeric receptor complex consisting of two molecules each of gp130 and either the membranebound IL-6Ra (classical signaling (10)) or the soluble receptor (s) IL-6Ra (trans-signaling (11)).”
BackgroundInterleukin 6 protects pancreatic β cells from apoptosis by stimulation of autophagy
Linnemann, A. K., Blumer, J. T., Marasco, M. R., Battiola, T. J., Umhoefer, H. M., Han, J. Y., Lamming, D. W., & Davis, D. B. (2017) · The FASEB Journal · doi:10.1096/fj.201700061rr · Cited by 103
“The IL-6 signaling cascade is activatedby the bindingof IL-6 to the IL-6 specific receptor, IL-6 receptor a (IL-6Ra), which causes recruitment of gp130 (12).”
BackgroundThe Role of the IL-6 Cytokine Family in Epithelial–Mesenchymal Plasticity in Cancer Progression
Abaurrea, A., Araujo, A. M., & Caffarel, M. M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22158334 · Cited by 112
“All IL-6-related cytokine receptor complexes transduce intracellular signals via the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway, but they can also activate the mitogen-activated protein kinase (MAPK)–extracellular signal-regulated kinase (MAPK/ERK) and phosphoinositide 3-kinase…”
BackgroundmTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice
Thiem, S., Pierce, T. P., Palmieri, M., Putoczki, T. L., Büchert, M., Preaudet, A., Farid, R., Love, C., Catimel, B., Lei, Z., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci65086 · Cited by 104
“Among these are IL-6 and IL-11, 2 IL-6 family cytokines that share the common receptor subunit GP130 and signal via JAK-mediated activation of STAT3 (8).”
Self-citationThe role of sex steroid hormones, cytokines and the endocannabinoid system in female fertility
Karasu, T., Marczylo, T. H., Maccarrone, M., & Konje, J. C. (2011) · Human Reproduction Update · doi:10.1093/humupd/dmq058 · Cited by 105
“after binding of the LIF receptor-b (LIF-Rb) to glycoprotein gp130 (Heinrich et al., 2003).”
BackgroundQuintana, A., Erta, M., Ferrer, B., Comes, G., Giralt, M., & Hidalgo, J. (2012) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2012.10.011 · Cited by 104
“…of IL-6, IL-11, IL-27, IL-31, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin 1 (CT-1), neuropoietin (NPN), cardiotrophin-like cytokine (CLC), and two IL-6 viral homologues (Bauer et al., 2007; Heinrich et al., 2003; Wang et al., 2009).”
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“Mol Cancer Ther; 16(10) October 2017 Molecular Cancer Therapeutics 2238”
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Interleukin-6 regulates hepatic transporters during acute-phase response
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“These cytokines are pleiotropic, sharing a glycoprotein chain gp130 as a common signal transducer [10,12,13].”
BackgroundHumoral factors in ALS patients during disease progression
Ehrhart, J. C., de Smith, A. J., Kuzmin‐Nichols, N., Zesiewicz, T., Jahan, I., Shytle, R. D., Kim, S.-H., Sanberg, C. D., Vu, T., Gooch, C. L., et al. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0350-4 · Cited by 106
“IL-6 is secreted by T lymphocytes and macrophages during infection, stimulating immune response [62–64] and serving as a pro-inflammatory mediator.”
BackgroundDietary isoflavones suppress endotoxin-induced inflammatory reaction in liver and intestine
Paradkar, P. N., Blum, P. S., Berhow, M. A., et al. (2004) · Cancer Letters · doi:10.1016/j.canlet.2004.05.019 · Cited by 103
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“It has been shown that IL-6 is the primary mediator of the fever induced by LPS [24].”
BackgroundRole of Transcription Factors in Peripheral Nerve Regeneration
Patodia, S., & Raivich, G. (2012) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2012.00008 · Cited by 107
“…and CNTF) requires a combination of various ligand binding units and a common signal-transducing unit gp130 (Taga and Kishimoto, 1995), through which they activate the JAK/STAT, Ras/MAPK, extracellular regulated-signal kinase (ERK), PI3K, and other pathways (Akira, 2000; Heinrich et al., 2003).”
BackgroundBoth STAT1 and STAT3 are favourable prognostic determinants in colorectal carcinoma
Gordziel, C., Bratsch, J., Moriggl, R., Knösel, T., & Friedrich, K. (2013) · British Journal of Cancer · doi:10.1038/bjc.2013.274 · Cited by 102
“Both STAT3 and STAT1 can become activated through the interleukin (IL)-6 receptor that consists of the IL-6 receptor a-chain and the gp130 cytokine receptor chain (Heinrich et al, 2003).”
BackgroundResultHundhausen, C., Roth, A., Whalen, E., Chen, J., Schneider, A., Long, S. A., Wei, S., Rawlings, R., Kinsman, M., Evanko, S. P., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aad9943 · Cited by 104
“ScienceTra IL-6 signals predominantly via the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway (8).”
BackgroundLee, H. H., Jung, J., Moon, A., Kang, H., & Cho, H. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20133143 · Cited by 101
“In addition, the activation of the PI3K-pAkt-mTOR pathway triggered by IL-6 was shown to be related to cell proliferation and metastasis in a variety of cancers [57,58].”
BackgroundYeoh, G. C., Ernst, M., Rose‐John, S., Akhurst, B., Payne, C. J., Long, S., Alexander, W. S., Croker, B. A., Grail, D., & Matthews, V. B. (2007) · Hepatology · doi:10.1002/hep.21535 · Cited by 103
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Role of Cytokine Signaling during Nervous System Development
Mousa, A., & Bakhiet, M. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms140713931 · Cited by 103
“LIF, CNTF, OSM, CT-1, NPN, and NNT-1, signal via gp130/LIF-R heterodimeric receptor complexes [57].”
BackgroundInfluentialYang, L., Li, B., Dang, E., Jin, L., Fan, X., & Wang, G. (2015) · Journal of Dermatological Science · doi:10.1016/j.jdermsci.2015.11.007 · Cited by 105
“In addition, it has been demonstrated that these pro-inflammatory cytokines can not only suppress the function of Tregs, but also induce the phosphorylation of STAT3 [17–19].”
Backgroundde Brito, R. D. C. C. M., Lucena‐Silva, N., Torres, L. C., Luna, C. F., Correia, J. B., & da Silva, G. A. P. (2016) · BMC Pulmonary Medicine · doi:10.1186/s12890-016-0324-z · Cited by 104
“cytokines IL-1, TNF and IL-6 are important for the acute phase response [7, 9, 25], while modulation of inflammatory responses of the airways is related to the expression of the anti-inflammatory cytokines,IL-10 and IL-4 [6, 8, 24].”
BackgroundAswani, A. D., Manson, J., Itagaki, K., Chiazza, F., Collino, M., Wupeng, W. L., Chan, T. K., Wong, W. S. F., Hauser, C. J., Thiemermann, C., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00891 · Cited by 102
“IL-6 exerts its action via the signal transducer gp130 leading to the activation of the STAT and MAPK cascades (47).”
BackgroundGagnon, J., Ramanathan, S., LeBlanc, C., Cloutier, A., McDonald, P. P., & Ilangumaran, S. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.12.7958 · Cited by 103
“Because IL-7 and IL-6 also stimulate the PI3K and MAPK pathways (35, 59), we examined whether pharmacological inhibitors of these signaling pathways would modulate the proliferation of CD8 T cells induced by cytokines.”
BackgroundCurrent Understanding of Rheumatoid Arthritis Therapy
Colmegna, I., Ohata, B., & Ménard, H. A. (2012) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2011.325 · Cited by 99
Molecular Aspects of the Stress Response: Chaperones, Membranes and Networks
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Brady Jennifer, J., Li, M., Suthram, S., Jiang, H., Wong, W. H., & Blau, H. M. (2013) · Nature Cell Biology · doi:10.1038/ncb2835 · Cited by 103
IL6 Gene Promoter Polymorphisms and Type 2 Diabetes
Huth, C., Heid, I. M., Vollmert, C., Gieger, C., Grallert, H., DiStefano, J. K., Langer, B., Thorand, B., Klopp, N., Hamid, Y. H., et al. (2006) · Diabetes · doi:10.2337/db06-0600 · Cited by 99
“IL-6 exerts crucial effects not only in inflammation and infection but also within the nervous and endocrine systems (1).”
Richards, P. J., Nowell, M. A., Horiuchi, S., McLoughlin, R. M., Fielding, C. A., Grau, S., Yamamoto, N., Ehrmann, M., Rose‐John, S., Williams, A. S., et al. (2006) · Arthritis & Rheumatism · doi:10.1002/art.21818 · Cited by 99
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“Since IL-6 is a pleiotropic cytokine which elucidates its cellular processes by activating not only STAT-3 but also other targets such as MAPK [43], the association of HIF-1a and VEGF with STAT-3 in our model was further confirmed by ectopic expression of STAT-3.”
Escobar, J., Pereda, J., Arduini, A., Sandoval, J., Sabater, L., Aparisi, L., López‐Rodas, G., & Sastre, J. (2009) · Current Pharmaceutical Design · doi:10.2174/138161209789058075 · Cited by 99
“Other cytokines, such as IL-6, also contribute to amplification of the acute-phase response in the inflammatory process through activation of MAP kinase cascades [213].”
BackgroundThe biology of interleukin-27 reveals unique pro- and anti-inflammatory functions in immunity
Aparicio-Siegmund, S., & Garbers, C. (2015) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2015.07.008 · Cited by 101
“Ligand binding and receptor complex formation lead to mutual activation of the associated Jaks and subsequent phosphorylation of intracellular tyrosine residues of gp130 and WSX-1 [21].”
BackgroundTseng-Rogenski, S. S., Hamaya, Y., Choi, D. H., & Carethers, J. M. (2014) · Gastroenterology · doi:10.1053/j.gastro.2014.11.027 · Cited by 97
“To delineate the cascade mechanism for the hMSH3 shift upon IL6 treatment, we employed flow cytometry and ELISA to examine the expression of IL6, mIL6R, and sIL6R.”
InfluentialSong, F., Zeng, K., Liao, L., Yu, Q., Tu, P., & Wang, X. (2016) · PLoS ONE · doi:10.1371/journal.pone.0149991 · Cited by 97
“Jaks are constitutively associated with the cytoplasmic side of membrane-spanning receptors [22].”
BackgroundRiethmüller, S., Ehlers, J. C., Lokau, J., Düsterhöft, S., Knittler, K., Dombrowsky, G., Grötzinger, J., Rabe, B., Rose‐John, S., & Garbers, C. (2016) · Scientific Reports · doi:10.1038/srep25550 · Cited by 105
Molecular Links between Central Obesity and Breast Cancer
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Local Drug Delivery Strategies towards Wound Healing
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Understanding Signaling Cascades in Melanoma†
Lopez‐Bergami, P., Fitchman, B., & Ronai, Z. A. (2007) · Photochemistry and Photobiology · doi:10.1111/j.1751-1097.2007.00254.x · Cited by 100
“These include dephosphorylation of the receptor complex or nuclear STAT dimers by PTPases, interaction of activated STATs with inhibitory molecules from the protein inhibitor of activated STAT family, and feedback inhibition of the pathway by suppressor of cytokine signaling (SOCS) proteins through inhibition and ⁄or…”
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Wolfrum, S., Teupser, D., Tan, M., Chen, K. Y., & Breslow, J. L. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709011104 · Cited by 93
The nuclear protein HMGB1, a new kind of chemokine?
Degryse, B., & de Virgilio, M. (2003) · FEBS Letters · doi:10.1016/s0014-5793(03)01027-5 · Cited by 96
Oncostatin M: a pleiotropic cytokine in the central nervous system
Chen, S., & Benveniste, E. N. (2004) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2004.06.002 · Cited by 97
“OSM is known to activate STAT1, STAT3 and STAT5 in a variety of cell types [2].”
BackgroundInfluentialInhibition of the JAK2/STAT3 Pathway Reduces Gastric Cancer Growth In Vitro and In Vivo
Judd, L. M., Menheniott, T. R., Ling, H. Y., Jackson, C. B., Howlett, M., Kalantzis, A., Priebe, W., & Giraud, A. S. (2014) · PLoS ONE · doi:10.1371/journal.pone.0095993 · Cited by 95
Cuadros, T., Trilla, E., Sarró, E., Vilà, M. R., Vilardell, J., de Torres, I. M., Salcedo, M., López-Hellín, J., Sánchez‐Pla, Á., y Cajal, S. R., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-1671 · Cited by 99
Molecular pathways in peritoneal fibrosis
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Iron and the liver: Update 2008
Deugnier, Y., Brissot, P., & Loréal, O. (2008) · Journal of Hepatology · doi:10.1016/j.jhep.2008.01.014 · Cited by 98
“– Another pathway whose activation leads to increased hepcidin production independently of HJV corresponds to the STAT3 pathway which is activated by interleukin 6 (IL-6) through JAK1/2 [20,21] and results in hepcidin transcription either directly or through the interaction between STAT 3 and SMAD [15].”
BackgroundHypoxic Preconditioning Induces Neuroprotective Stanniocalcin-1 in Brain via IL-6 Signaling
Westberg, J. A., Serlachius, M., Lankila, P., Penkowa, M., Hidalgo, J., & Andersson, L. C. (2007) · Stroke · doi:10.1161/01.str.0000258113.67252.fa · Cited by 95
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The clinical relevance of OSM in inflammatory diseases: a comprehensive review
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Holtick, U., Vockerodt, M., Pinkert, D., Schoof, N., Stürzenhofecker, B., Kussebi, N., Lauber, K., Wesselborg, S., Löffler, D., Horn, F., et al. (2005) · Leukemia · doi:10.1038/sj.leu.2403750 · Cited by 94
Crystal Structure of the Entire Ectodomain of gp130
Xu, Y., Kershaw, N. J., Luo, C. S., Soo, P., Pocock, M. J., Czabotar, P. E., Hilton, D. J., Nicola, N. A., Garrett, T., & Zhang, J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.c110.129502 · Cited by 100
Fahmi, A., Smart, N., Punn, A., Jabr, R. I., Marber, M. S., & Heads, R. J. (2012) · Cellular Signalling · doi:10.1016/j.cellsig.2012.12.008 · Cited by 96
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“Binding of IL6 to CD126 and their association with GP130 triggers the activation of Janus kinases (JAK), which phosphorylate STAT3, thus modulating the expression of a broad spectrum of downstream target genes (9).”
BackgroundFunctional Role and Therapeutic Potential of the Pim-1 Kinase in Colon Carcinoma
Weirauch, U., Beckmann, N., Thomas, M., Grünweller, A., Huber, K., Bracher, F., Hartmann, R. K., & Aigner, A. M. (2013) · Neoplasia · doi:10.1593/neo.13172 · Cited by 96
“STAT3 has been described previously to be involved in the regulation of Pim-1 [3,4] and of survivin expression [26].”
BackgroundStat3 as a Potential Target for Cancer Immunotherapy
Kortylewski, M., & Yu, H. (2007) · Journal of Immunotherapy · doi:10.1097/01.cji.0000211327.76266.65 · Cited by 94
Varela, M., Dios, S., Novoa, B., & Figueras, A. J. (2011) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2011.11.004 · Cited by 93
The future of EPAC-targeted therapies: agonism versus antagonism
Parnell, E., Palmer, T. M., & Yarwood, S. J. (2015) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2015.02.003 · Cited by 92
“Signalling by IL-6 occurs through an IL-6 receptor (IL-6R) complex comprising an IL-6-binding a chain (IL-6R a ) and gp130, which interacts with IL-6R a [48] (Figure 4).”
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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