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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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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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In the paper
“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 the paper
“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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“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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- Not matchedcites [45]
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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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- Not matchedcites [55]
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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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- Not matchedcites [59]
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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
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- Not matchedcites [49]
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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.
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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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
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Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
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Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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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
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- Not matchedcites [108]
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- 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.
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- 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.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably 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.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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?
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
Strength:plain· not yet calibratedn = 8Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. 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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- 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.
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- 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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.”
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“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
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“SHP-2 acts as a phosphatase for the (IL6-gp80-gp130-JAK*)2 complex and inactivates it (Heinrich et al., 1998, 2003; Levy and Darnell, 2002; ten Hoeve et al., 2002).”
BackgroundMethodInfluentialWatterson, T. L., Sorensen, J., Martin, R. S., & Coulombe, R. A. (2007) · Journal of Toxicology and Environmental Health · doi:10.1080/15287390701457746 · Cited by 81
“Both differential splicing and proteolytic cleavage contribute to the production of sIL-6R, although the cause is poorly understood ( Heinrich et al, 1998 , 2003 ; Jones et al, 2001 ; Muller-Newen et al, 1998 ).”
BackgroundMultifarious Determinants of Cytokine Receptor Signaling Specificity
Moraga, I., Spangler, J. B., Mendoza, J. L., & García, K. C. (2014) · Advances in immunology · doi:10.1016/b978-0-12-800100-4.00001-5 · Cited by 79
“In addition to their signaling through the Jak/STAT pathway, some cytokines can also activate the Akt and Erk pathways (Platanias, 2005), as well as other signaling networks (Gough, Levy, Johnstone, & Clarke, 2008; Heinrich et al., 2003; Malek, 2008; Schindler, Levy, & Decker, 2007; van BoxelDezaire, Rani, & Stark, 20…”
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LIF-STAT signaling and trophoblast biology
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Polyphenols from blueberries modulate inflammation cytokines in LPS-induced RAW264.7 macrophages
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Calcium-Sensing Receptor Gene: Regulation of Expression
Hendy, G. N., & Canaff, L. (2016) · Frontiers in Physiology · doi:10.3389/fphys.2016.00394 · Cited by 83
Dolatabadi, S., Jonasson, E., Lindén, M., Fereydouni, B., Bäcksten, K., Nilsson, M. S., Martner, A., Forootan, A., Fagman, H., Landberg, G., et al. (2019) · International Journal of Cancer · doi:10.1002/ijc.32123 · Cited by 77
“signalling The JAK–STAT pathway can be activated by IL6-type cytokines through dimerization of receptors, including GP130, IL6 and LIF receptors.(27) Using flow cytometry, we observed high expression of LIFR, intermediate expression of GP130, and no or minor expression of IL6R in MLS cell lines (Fig.”
BackgroundSturiale, C. L., Puca, A., Sebastiani, P., Gatto, I., Albanese, A., Rocco, C. D., Maira, G., & Pola, R. (2012) · Brain · doi:10.1093/brain/aws180 · Cited by 76
“IL6 expression is largely regulated at the level of transcription (Heinrich et al., 2003).”
BackgroundHsa_circ_0005519 increases IL‐13/IL‐6 by regulating hsa‐let‐7a‐5p in CD4+ T cells to affect asthma
Huang, Z., Cao, Y., Zhou, M., Qi, X., Fu, B., Mou, Y., Wu, G., Xie, J., Zhao, J., & Xiong, W. (2019) · Clinical & Experimental Allergy · doi:10.1111/cea.13445 · Cited by 77
A Critical Update of the Assessment and Acute Management of Patients with Severe Burns
Lang, T. C., Zhao, R., Kim, A. S., Wijewardena, A., Vandervord, J. G., Xue, M., & Jackson, C. (2019) · Advances in Wound Care · doi:10.1089/wound.2019.0963 · Cited by 78
Culos, A., Tsai, A. S., Stanley, N., Becker, M., Ghaemi, M. S., McIlwain, D. R., Fallahzadeh, R., Tanada, A., Nassar, H., Espinosa, C. A., et al. (2020) · Nature Machine Intelligence · doi:10.1038/s42256-020-00232-8 · Cited by 76
Reappraisal of Adipose Tissue Inflammation in Obesity
Engin, A. (2024) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-63657-8_10 · Cited by 86
Zigmond, R. E. (2012) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2011.00062 · Cited by 77
“Nevertheless, one hypothesis is that the IL-31 receptor α arose by gene duplication of gp130 and that it retains many of the functions of the latter such as binding to Janus kinases (JAKs) and Signal Transducers and Activators of Transcription (STAT), a signal pathway discussed in more detail below (Cornelissen et al.…”
BackgroundSchmieder, A., Multhoff, G., & Radons, J. (2012) · Cytokine · doi:10.1016/j.cyto.2012.06.286 · Cited by 77
Qing, Y., Costa‐Pereira, A. P., Watling, D., & Stark, G. R. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m409863200 · Cited by 78
Airway epithelial cell signaling in response to bacterial pathogens
Gómez, M. I., & Prince, A. S. (2007) · Pediatric Pulmonology · doi:10.1002/ppul.20735 · Cited by 77
“Epithelial responsiveness to IL-6 is dependent upon the presence of two receptors, gp130 and IL-6Ra (gp80).(99,100) Shed soluble IL-6Ra binds to IL-6 forming a ligand-receptor complex that interacts with membrane bound gp130 in a high affinity interaction termed ‘‘trans-signaling.”
BackgroundIL-11 Regulates Autoimmune Demyelination
Gurfein, B. T., Zhang, Y., López, C. B., Argaw, A. T., Zameer, A., Moran, T. M., & John, G. R. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0900622 · Cited by 79
“Family members have pro- as well as antiinflammatory properties and are important regulators of hematopoiesis, as well as innate and adaptive immune responses (32).”
BackgroundShum, A. M. Y., Mahendradatta, T., Taylor, R., Painter, A., Moore, M. M., Tsoli, M., Tan, T. C., Clarke, S. J., Robertson, G. R., & Polly, P. (2012) · Aging · doi:10.18632/aging.100436 · Cited by 77
“IL-6 mediates its action via IL-6 receptor (IL-6RA) which heterodimerizes with the gp130 partner [18].”
BackgroundDiao, Y., Wang, X., & Wu, Z. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.00267-09 · Cited by 76
“4B and analyzed the activation status of JAK1, LIFR, and gp130, as these are essential upstream molecules indispensable for the LIF-induced STAT1/3 activation (15, 25, 36).”
BackgroundSchuurs, T. A., Gerbens, F., van der Hoeven, J. A. B., Ottens, P. J., Kooi, K. A., Leuvenink, H. G. D., Hofstra, R. M. W., & Ploeg, R. J. (2004) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2004.00607.x · Cited by 76
“Some of these, such as Il-1b, Il-6 and SOCS-3, have shown to influence again the expression and activity of cytokines, transcription factors and signal transduction proteins (28,40,41).”
BackgroundPei, T., Meng, Q., Han, J., Sun, H., Li, L., Song, R., Sun, B., Pan, S., Liang, D., & Liu, L. (2016) · Oncotarget · doi:10.18632/oncotarget.9782 · Cited by 80
Chua, A. C. G., Klopcic, B. R. S., Ho, D. S., Fu, S. K., Forrest, C. H., Croft, K. D., Olynyk, J. K., Lawrance, I. C., & Trinder, D. (2013) · PLoS ONE · doi:10.1371/journal.pone.0078850 · Cited by 76
“As IL-6 and IL-11 are activators of the transcription factor, Stat3, intracelluar signaling is initiated when they bind to their respective receptors and associate with gp130 triggering Stat3 activation via Jak[32] within the colonic mucosa.”
BackgroundThe oncostatin M‐stromal cell axis in health and disease
West, N. R., Owens, B. M. J., & Hegazy, A. N. (2018) · Scandinavian Journal of Immunology · doi:10.1111/sji.12694 · Cited by 77
“The ability of OSM to transduce signals via two distinct receptor chains (gp130 and OSMR) gives it a broad signal transduction profile in comparison to IL‐6, which relies solely on gp130 for signalling (Figure 2).(18,19,37) While JAK1 is essential for IL‐6 signalling, OSM signals are propagated by both JAK1 and JAK2.”
BackgroundWest, N. R., & Watson, P. H. (2010) · Oncogene · doi:10.1038/onc.2009.488 · Cited by 76
Interleukin 6 promoter polymorphisms influence the outcome of chronic hepatitis C
Cussigh, A., Falleti, E., Fabris, C., Bitetto, D., Cmet, S., Fontanini, E., Bignulin, S., Fornasiere, E., Fumolo, E., Minisini, R., et al. (2010) · Immunogenetics · doi:10.1007/s00251-010-0491-7 · Cited by 75
“There are two IL-6 signaling pathways (Heinrich et al. 2003; Naugler and Karin 2008; Scheller and Rose-John 2006).”
Terui, K., Enosawa, S., Haga, S., Zhang, H. Q., Kuroda, H., Kouchi, K., Matsunaga, T., Yoshida, H., Engelhardt, J. F., Irani, K., et al. (2004) · Journal of Hepatology · doi:10.1016/j.jhep.2004.08.019 · Cited by 76
“These anti-apoptotic properties of IL-6 family proteins seem to result primarily from activating downstream signaling molecules including Jak/Stat, MAPK and phosphatidylinositol 3-kinase (PI3-K) [37], but it still remains unclear which pathways are most critically involved.”
Parameter set selection for estimation of nonlinear dynamic systems
Chu, Y., & Hahn, J. (2007) · AIChE Journal · doi:10.1002/aic.11295 · Cited by 76
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Targeting interlukin-6 to relieve immunosuppression in tumor microenvironment
Liu, Q., Yu, S., Li, A., Xu, H., Han, X., & Wu, K. (2017) · Tumor Biology · doi:10.1177/1010428317712445 · Cited by 76
Dreuw, A., Hermanns, H. M., Heise, R., Joussen, S., Rodríguez, F., Marquardt, Y., Jugert, F. K., Merk, H. F., Heinrich, P. C., & Baron, J. M. (2005) · Journal of Investigative Dermatology · doi:10.1111/j.0022-202x.2004.23499.x · Cited by 76
Self-citationModulation of prostate cancer growth in bone microenvironments
Edlund, M., Sung, S., & Chung, L. W. K. (2003) · Journal of Cellular Biochemistry · doi:10.1002/jcb.10702 · Cited by 80
“…stromal fibroblasts or myofibroblasts to the tumor [Tuxhorn et al., 2002a,b,c; Zidar et al., 2002], and (3) alter microenvironements adjacent to the tumor, through inflammatory and immune-responsive cell secretion of cyto- and chemokines [Svennevig, 1980; Heinrich et al., 2003; Wang et al., 2003].”
BackgroundHuang, Y., Yang, H., Huang, S.-W., Ou, G., Hsu, Y.-F., & Hsu, M. (2016) · PLoS ONE · doi:10.1371/journal.pone.0158839 · Cited by 77
“IL-6 signaling complex activates mainly three major downstream signaling cascades including the janus tyrosine family kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signaling, the phosphoinositide 3-kinase (PI3-K) signaling, and the Ras-extracellular signal-regulated kinase (ERK) signaling [27…”
BackgroundCD44 in Ovarian Cancer Progression and Therapy Resistance—A Critical Role for STAT3
Martincuks, A., Li, P.-C., Zhao, Q., Zhang, C., Li, Y., Yu, H., & Rodrı́guez-Rodrı́guez, L. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.589601 · Cited by 79
“In turn, well known STAT3 activators IL-6 (84) and IGF-1 (85) have been shown to significantly induce CD44 promoter activity in pancreatic tumor cells (12), while in hepatocytes several putative STAT3 binding sites have been described within the CD44 promoter, demonstrating that STAT3 can directly induce CD44 expressi…”
BackgroundInfluentialParakh, S., Ernst, M., & Poh, A. R. (2021) · Cancers · doi:10.3390/cancers13246228 · Cited by 77
“Seven STAT family members have been identified, and include STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6 [14].”
BackgroundLeukemia Inhibitory Factor: An Important Cytokine in Pathologies and Cancer
Jorgensen, M. M., & de la Puente, P. (2022) · Biomolecules · doi:10.3390/biom12020217 · Cited by 79
“The main kinase targeted by LIF is thought to be JAK1, which stimulates the JAK/STAT, MAPK, and PI3K pathways (Figure 6) [77,78].”
BackgroundAteghang, B., Wartenberg, M., Gassmann, M., & Sauer, H. (2006) · Journal of Cell Science · doi:10.1242/jcs.02798 · Cited by 76
“In this respect, the data of the current study demonstrated stimulation of gp130 protein expression as well as phosphorylation by prooxidants and chemical hypoxia, and downstream activation of several members of the previously described (Heinrich et al., 2003), CT-1 activated signal transduction cascade, i.”
BackgroundUpdate on the role of leukemia inhibitory factor in assisted reproduction
Aghajanova, L. (2010) · Current Opinion in Obstetrics & Gynecology · doi:10.1097/gco.0b013e32833848e5 · Cited by 75
Chipoy, C., Berreur, M., Couillaud, S., Pradal, G., Vallette, F. M., Colombeix, C., Rédiní, F., Heymann, D., & Blanchard, F. (2004) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.040817 · Cited by 75
“6A), as observed previously in various other cell lines.((29)) Similar results were”
ResultCaiello, I., Minnone, G., Holzinger, D., Vogl, T., Prencipe, G., Manzo, A., Benedetti, F. D., & Strippoli, R. (2014) · PLoS ONE · doi:10.1371/journal.pone.0107886 · Cited by 75
“In all experiments, we used IL-6 in combination with the sIL-6R (IL-6/sIL-6R) in order to obtain a response also in cells expressing gp130, but not membrane IL-6 receptor (IL-6R) [2].”
BackgroundMethodMembrane-associated STAT3 and PY-STAT3 in the Cytoplasm
Shah, M., Patel, K., Mukhopadhyay, S., Xu, F., Guo, G. G., & Sehgal, P. B. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m508527200 · Cited by 75
Gupta, G. K., Agrawal, T., DelCore, M. G., Mohiuddin, S. M., & Agrawal, D. K. (2012) · Experimental and Molecular Pathology · doi:10.1016/j.yexmp.2012.04.006 · Cited by 79
“Tyrosine kinase family JAK activation and subsequent activation of STAT are key events in signal transduction of different cytokines and growth factors (Heinrich et al., 2003; Ihle, 2001).”
BackgroundInflammatory Networks in the Control of Spermatogenesis
O’Bryan, M. K., & Hedger, M. P. (2009) · Advances in experimental medicine and biology · doi:10.1007/978-0-387-09597-4_6 · Cited by 75
“Interleukin 6 is a member of an important family of mediators involved in the regulation of the acute-phase response to injury and infection, which exert their action via binding to specific receptors that associate with a common membrane signal transducer gp130, leading to the activation of the Jak/Stat and MAP kinas…”
BackgroundCabral‐Santos, C., Castrillón, C. I. M., Miranda, R. A. T., Monteiro, P. A., Inoue, D. S., Campos, E. Z., Hofmann, P., & Lira, F. S. (2016) · Frontiers in Physiology · doi:10.3389/fphys.2016.00509 · Cited by 79
“IL-6 is an important mediator involved in the regulation of the acute-phase response to injury and infection (Heinrich et al., 2003).”
Meyer, P., Maity, P., Burkovski, A., Schwab, J. D., Müssel, C., Singh, K., Ferreira, F. F., Krug, L., Maier, H. J., Wlaschek, M., et al. (2017) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1005741 · Cited by 76
Ishiguro, H., Akimoto, K., Nagashima, Y., Kojima, Y., Sasaki, T., Ishiguro-Imagawa, Y., Nakaigawa, N., Ohno, S., Kubota, Y., & Uemura, H. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0907044106 · Cited by 74
“We next examined the effect of aPKC / depletion on phosphorylation of STAT3, one of the downstream mediators of the possible IL-6 involvement in prostate cancer cells (25, 29, 32, 33).”
BackgroundSkin changes in streptozotocin-induced diabetic rats
de Andrade, T. A. M., Masson‐Meyers, D. S., Caetano, G. F., Terra, V. A., Ovídio, P. P., Jordão, A. A., & Frade, M. A. C. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.06.166 · Cited by 76
Oncostatin M receptor is a novel therapeutic target in cervical squamous cell carcinoma
Caffarel, M. M., & Coleman, N. (2013) · The Journal of Pathology · doi:10.1002/path.4305 · Cited by 75
“Following OSM binding, OSMR signals mainly through the JAK/STAT pathway, but also activates MAPK/ERK and PI3K/AKT cascades, inducing the transcription of context-dependent target genes [21,22].”
BackgroundInfluentialEmerging Mechanisms of Immunosuppression in Oral Cancers
Jewett, A., Head, C. S., & Cacalano, N. A. (2006) · Journal of Dental Research · doi:10.1177/154405910608501201 · Cited by 74
Fallarino, F., Orabona, C., Vacca, C., Bianchi, R., Gizzi, S., Asselin‐Paturel, C., Fioretti, M. C., Trinchieri, G., Grohmann, U., & Puccetti, P. (2005) · International Immunology · doi:10.1093/intimm/dxh321 · Cited by 76
“Although SOCS3 expression is typically induced by IL-6 to attenuate its own signaling ( 33 ), up-regulation of SOCS3 by IL-6 may be responsible for inhibition of STAT-dependent signaling by IFNs (34).”
BackgroundOncostatin M Promotes Mammary Tumor Metastasis to Bone and Osteolytic Bone Degradation
Bolin, C., Tawara, K., Sutherland, C., Redshaw, J. D., Aranda, P., Moselhy, J., Anderson, R. L., & Jorcyk, C. L. (2012) · Genes & Cancer · doi:10.1177/1947601912458284 · Cited by 74
“Breast cancer-derived bone metastasis leads to the dysregulation of IL-6, IL-11, and various growth factors such as receptor activator of NFB (RANKL), macrophage-colony stimulating factor (MCSF), and VEGF by different cell types including osteoblasts, stromal cells, and immune cells (4, 23, 32, 33).”
Neuroendocrine-immune interactions in teleost fish
Kemenade, B. M. L. V.-V., Stolte, E. H., Metz, J. R., & Chadzińska, M. (2009) · Cited by 74
Radiation driven epithelial-mesenchymal transition is mediated by Notch signaling in breast cancer
Kim, R.-K., Kaushik, N., Suh, Y., Yoo, K.-C., Cui, Y., Kim, M.-J., Lee, H., Kim, I. G., & Lee, S. (2016) · Oncotarget · doi:10.18632/oncotarget.10802 · Cited by 74
“Because the signal transduction of IL-6 is involved in the activation of JAK leading to the activation of transcription factor STAT3 [28], we questioned if a certain secretion factor secreted by radiation could induce EMT.”
BackgroundCD200, a “no danger” signal for hair follicles
Rosenblum, M. D., Yancey, K. B., Olasz, E. B., & Truitt, R. L. (2006) · Journal of Dermatological Science · doi:10.1016/j.jdermsci.2005.11.003 · Cited by 74
IL-6 activates serum and glucocorticoid kinase via p38α mitogen-activated protein kinase pathway
Meng, F., Yamagiwa, Y., Taffetani, S., Han, J., & Patel, T. C. (2005) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00081.2005 · Cited by 74
“Although signaling pathways mediating proliferative responses by IL-6 are well characterized, signaling for cell survival remains poorly understood (20, 21).”
BackgroundLin, M., Lee, D.-D., Liu, T. T., Lin, Y.-F., Chen, S.-Y., Huang, C.-C., Weng, H., Liu, Y. F., Tanaka, A., Arita, K., et al. (2009) · European Journal of Human Genetics · doi:10.1038/ejhg.2009.135 · Cited by 72
Oncogene Mimicry as a Mechanism of Primary Resistance to BRAF Inhibitors
Sos, M. L., Levin, R. S., Gordan, J. D., Osés-Prieto, J. A., Webber, J. T., Salt, M. B., Hann, B. C., Burlingame, A. L., McCormick, F. P., Bandyopadhyay, S., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.07.010 · Cited by 72
“Because cytokines such as IL-6 are known activators of STAT3 signaling, we hypothesized that an autocrine loop might be responsible for the time-dependent activation of JAK/STAT signaling (Heinrich et al., 2003).”
Fang, X., Hong, Y., Dai, L., Qian, Y., Zhu, C., Wu, B., & Li, S. (2017) · Molecular Carcinogenesis · doi:10.1002/mc.22691 · Cited by 73
“The signal transduction of IL-6 is involved in the activation of JAK/STAT3 signaling.(30) Dysregulation of the IL-6-mediated JAK/STAT3 signaling pathway is closely related to the development of diverse human solid tumors including CRC.”
BackgroundOncostatin M, an Underestimated Player in the Central Nervous System
Houben, E., Hellings, N., & Broux, B. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01165 · Cited by 73
Active roles of dysfunctional vascular endothelium in fibrosis and cancer
Hsu, T., Nguyen-Tran, H.-H., & Trojanowska, M. (2019) · Journal of Biomedical Science · doi:10.1186/s12929-019-0580-3 · Cited by 76
Zacks, D. N., Han, Y., Zeng, Y., & Swaroop, A. (2006) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.05-1209 · Cited by 73
“Similar to IL-6, CNTF also binds to an -receptor, but this complex then binds to a heterodimer, composed of one gp130 subunit and one LIF (leukemia inhibitory factor) receptor subunit.(14) In our model, the LIF receptor was marginally upregulated by only approximately 1.”
BackgroundInfluentialAre STATS Arginine-methylated?
Komyod, W., Bauer, U., Heinrich, P. C., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.c400606200 · Cited by 73
Self-citationLeukemia inhibitory factor tips the immune balance towards regulatory T cells in multiple sclerosis
Janssens, K., den Haute, C. V., Baekelandt, V., Lucas, S., van Horssen, J., Somers, V. A., Wijmeersch, B. V., Stinissen, P., Hendriks, J. J. A., Slaets, H., et al. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2014.11.010 · Cited by 73
Aggravation by prostaglandin E2 of interleukin-6-dependent insulin resistance in hepatocytes #
Henkel, J., Neuschäfer‐Rube, F., Pathe‐Neuschäfer‐Rube, A., & Püschel, G. P. (2009) · Hepatology · doi:10.1002/hep.23064 · Cited by 74
Hashizume, M., & Mihara, M. (2010) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2010.10.135 · Cited by 76
O’Malley, D., Liston, M., Hyland, N. P., Dinan, T. G., & Cryan, J. F. (2010) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00385.2010 · Cited by 73
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“Signal transduction (Heinrich et al. 2003) is initiated by Janus kinases (JAKs) that engage the MAPK, signal transducer and activator of transcription 3 (STAT3) and phosphatidylinositol-3kinase (PI3K (PIK3CA)) pathways, each of which has documented roles in breast tumour pathogenesis (Clevenger…”
BackgroundInfluentialFurusawa, J.-I., Mizoguchi, I., Chiba, Y., Hisada, M., Kobayashi, F., Yoshida, H., Nakae, S., Tsuchida, A., Matsumoto, T., Ema, H., et al. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005507 · Cited by 76
“It was recently reported that IL-6Rα-deficient mice show increased resistance to P. chabaudi infection and that IL-6 trans-signaling, but not IL-6 classic signaling, contributes to a lethal outcome of infection [60].”
BackgroundInfluentialSignal transduction and Th17 cell differentiation
O'Shea, J. J., Steward-Tharp, S. M., Laurence, A., Watford, W. T., Wei, L., Adamson, A. S., & Fan, S. (2009) · Microbes and Infection · doi:10.1016/j.micinf.2009.04.007 · Cited by 73
“Induction of IL-6 is a part of the acute phase response during severe infection, but it is now known to be produced by many immune and non-immune cells (Heinrich et al. 2003; Kishimoto 2005).”
BackgroundNaseem, S., Hussain, T., & Manzoor, S. (2018) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2018.01.002 · Cited by 72
Effects and mechanisms of pyrethroids on male reproductive system
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Gómez, M. I., Sokol, S., Muir, A. B., Soong, G., Bastien, J., & Prince, A. S. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.3.1930 · Cited by 72
“Epithelial responsiveness to IL-6 is dependent upon the presence of two potential receptors, the ubiquitously expressed gp130 and IL-6R (gp80), which is more limited in its distribution (8, 10).”
BackgroundCytokine regulation of immune responses to Porphyromonas gingivalis
Taylor, J. J. (2010) · Periodontology 2000 · doi:10.1111/j.1600-0757.2009.00344.x · Cited by 73
“gp130 signaling cytokines Leukocyte differentiation and growth, acute-phase reactions IL-6; IL-11; LIF; oncostatin M (116, 269)”
Thyroid hormone preconditioning: Protection against ischemia-reperfusion liver injury in the rat
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Structure-guided Optimization of the Interleukin-6 Trans-signaling Antagonist sgp130
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“IL-6 binds to the specific IL-6 receptor (IL-6R), and this complex associates with two molecules of the ubiquitously expressed gp130 (Taga and Kishimoto, 1995; Heinrich et al., 2003).”
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“In most cell types, IL11 mediates its effects through the JAK / STAT signaling pathway primarily via STAT3 [54].”
BackgroundLeukemia Inhibitory Factor Signaling Is Required for Lung Protection during Pneumonia
Quinton, L. J., Mizgerd, J. P., Hilliard, K. L., Jones, M. R., Kwon, C. Y., & Allen, E. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1200256 · Cited by 70
Metformin inhibits IL-6 signaling by decreasing IL-6R expression on multiple myeloma cells
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“unlike IL-6ST which is a shared receptor for other cytokines [10, 11].”
BackgroundReactive Oxygen Species: A Double-Edged Sword in the Modulation of Cancer Signaling Pathway Dynamics
Nigam, M., Punia, B., Dimri, D. B., Mishra, A. P., Radu, A.-F., & Bungau, G. S. (2025) · Cells · doi:10.3390/cells14151207 · Cited by 83
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“receptor complex consisted of IL-6R and gp130 [10], and then activates signal transducer and activator of transcription 3 (STAT3) via Januskinases (JAKs), and phosphorylated STAT3 at Y705 (p-STAT3 (Y705)) [11], p-STAT3 (Y705) monomers combine with each other, form dimers to translocate into the nucleus and bind to cog…”
BackgroundEndogenous IL-11 Signaling Is Essential in Th2- and IL-13–Induced Inflammation and Mucus Production
Lee, C. G., Hartl, D., Matsuura, H., Dunlop, F., Scotney, P. D., Fabri, L., Nash, A. D., Chen, N., Tang, C., Chen, Q., et al. (2008) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2008-0053oc · Cited by 71
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“All three carp p40 proteins contain the C-terminal WSXWS consensus motif that is characteristic for type I cytokine receptors (Heinrich et al., 2003).”
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Interleukin‐27 displays interferon‐γ–like functions in human hepatoma cells and hepatocytes†
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Interleukin‐6 role in head and neck squamous cell carcinoma progression
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“Other members of IL-6 family include IL-11, leukemia inhibitory factor (LIF), ciliar neurotrophic factor (CTNF), oncostatin M (OSM), cardiotrophin-1 (CT-1) and cardiotrophin like cytokine (CLC).(46,47) IL-6 mediates its signaling by binding to an 80 kDa type-1 cell surface cytokine a-receptor subunit (IL6R; also known…”
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“JAK1, JAK2, JAK3, and TYK2 have been linked to the activation of STAT3 [10,11].”
BackgroundThe Cytokine Receptor gp130: Faithfully Promiscuous
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“LIF uses a heterodimer of gp130 and LIFR to transduce signals, and OSM uses a heterodimer of gp130 and OSMR (3).”
BackgroundSelf-citationMechanisms of the Hepatic Acute-Phase Response during Bacterial Pneumonia
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“(17), phosphorylation of STAT3 (pSTAT3) in the liver was analyzed by immunoblotting throughout 24 h of E.”
MethodType I interferons regulate susceptibility to inflammation-induced preterm birth
Cappelletti, M., Presicce, P., Lawson, M. J., Chaturvedi, V., Stankiewicz, T. E., Vanoni, S., Harley, I. T. W., McAlees, J. W., Giles, D. A., Moreno‐Fernandez, M. E., et al. (2017) · JCI Insight · doi:10.1172/jci.insight.91288 · Cited by 71
“Both type I IFN and IL-6 signaling activate STAT3 (79, 80), while LPS stimulation in myeloid cells is known to induce expression of the transcription factors C/EBP-β and NF-κB, which regulate IL-6 production (81).”
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Prospects for mTOR-mediated functional repair after central nervous system trauma
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“To determine if miR-17-5p specifically modulates this pathway to activate astrocytes in the spinal cord, we treated our astroglial cultures with LIF that is known to activate JAK/STAT3 pathway through binding to LIFR/gp130 receptor complex (Heinrich et al., 2003).”
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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