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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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Effect of obesity on pulmonary inflammation induced by acute ozone exposure: role of interleukin-6
Lang, J. E., Williams, E. S., Mizgerd, J. P., & Shore, S. A. (2008) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00122.2007 · Cited by 54
“Many of the downstream effects of IL-6 cytokine family activation are mediated through activation of signal transducer and activation of transcription 3 (STAT-3) (20).”
BackgroundJamip1 (Marlin-1) Defines a Family of Proteins Interacting with Janus Kinases and Microtubules
Steindler, C., Li, Z., Algarté-Génin, M., Alcover, A., Libri, V., Ragimbeau, J., & Pellegrini, S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m401915200 · Cited by 54
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“It has been found that IL-6 induces intracellular signaling cascades that give rise to inflammatory cytokine production (22).”
BackgroundRuwanpura, S. M., McLeod, L., Dousha, L. F., Seow, H. J., Alhayyani, S., Tate, M. D., Deswaerte, V., Brooks, G. D., Bozinovski, S., MacDonald, M., et al. (2016) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201512-2368oc · Cited by 54
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“…gp130, stimulate several intracellular signaling including the Janus Kinase/ Signal Transducer and Activator of Transcription (JAK/STAT), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3- kinase/protein kinase B (PI3K/Akt) pathways (Boulanger et al., 2003; Heinrich et al., 2003).”
BackgroundWhitley, S. K., Balasubramani, A., Zindl, C. L., Sen, R., Shibata, Y., Crawford, G. E., Weathington, N. M., Hatton, R. D., & Weaver, C. T. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.002721 · Cited by 58
“Whereas neither IL-6, IL-21, nor IL-23 alone can elicit IL-17 production from Th17 effector cells (12, 13), in combination with IL-1 these cytokines are powerful inducers of IL-17.”
BackgroundProtective role of wogonin against lipopolysaccharide-induced angiogenesis via VEGFR-2, not VEGFR-1
Lin, C.-M., Chang, H., Chen, Y., et al. (2006) · International Immunopharmacology · doi:10.1016/j.intimp.2006.07.003 · Cited by 54
Role of IL-6 signalling in Polycystic Ovarian Syndrome associated inflammation
Borthakur, A., Prabhu, Y. D., & Gopalakrishnan, A. V. (2020) · Journal of Reproductive Immunology · doi:10.1016/j.jri.2020.103155 · Cited by 53
3′,5′-Cyclic diguanylic acid elicits mucosal immunity against bacterial infection
Yan, H., KuoLee, R., Tram, K., et al. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.07.061 · Cited by 53
Vollmer, S., Kappler, V., Kaczor, J., Flügel, D., Rolvering, C., Kato, N., Kietzmann, T., Behrmann, I., & Haan, C. (2009) · Hepatology · doi:10.1002/hep.22928 · Cited by 54
Self-citationSugimoto, M., Ohno, T., Graham, D. Y., & Yamaoka, Y. (2011) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2011.06817.x · Cited by 54
Yeh, K., Li, Y., Hsieh, L., Lu, C. H., Chou, W., Liaw, C., Tang, R., & Liao, S. (2010) · Japanese Journal of Clinical Oncology · doi:10.1093/jjco/hyq010 · Cited by 53
“Poorly undifferentiated (3) 2 1 0 3 CEA (mg/l) 43.”
The role of gp130 receptor cytokines in the regulation of metabolic homeostasis
Cron, L., Allen, T. L., & Febbraio, M. A. (2016) · Journal of Experimental Biology · doi:10.1242/jeb.129213 · Cited by 53
“In this process, these researchers produced seven recombinant human cytokines by removing one of the gp130 binding epitopes of IL-6 on site III and replacing it with the LIFR epitope from CNTF on site III (Kallen et al., 1999).”
BackgroundInfluentialLi, Z., Chen, J., Zhou, Z., et al. (2017) · Tumor Biology · doi:10.1177/1010428317705335 · Cited by 53
Zhao, D., Han, D., Wang, S., Lv, B., Wang, X., & Ma, C. (2019) · Molecular Pain · doi:10.1177/1744806919857981 · Cited by 55
“After activation, gp130 acts via stimulation of the MAPK pathway and classical JAKSTAT signaling.(40) In addition to transcriptional regulation, IL-6 has been shown to control protein synthesis of DRG neurons and thereby alter mechanical allodynia.”
MethodPlatelets as Potent Signaling Entities in Type 2 Diabetes Mellitus
Pretorius, E. (2019) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2019.05.003 · Cited by 53
Oshima, K., Teo, D. T. W., Senn, P., Starlinger, V., & Heller, S. (2007) · BMC Developmental Biology · doi:10.1186/1471-213x-7-112 · Cited by 56
“Other known cytokines signaling via the same principal pathway are ciliary neurotrophic factor, interleukin-6, interleukin-11, oncostatinM, cardiotrophin-1, and cardiotrophin-like cytokine [19].”
Backgroundc‐myc as a mediator of accelerated apoptosis and involution in mammary glands lacking Socs3
Sutherland, K. D., Vaillant, F., Alexander, W. S., Wintermantel, T. M., Forrest, N. C., Holroyd, S. L., McManus, E. J., Schütz, G., Watson, C. J., Chodosh, L. A., et al. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601455 · Cited by 54
“Oncostatin M (OSM) induces heterodimerisation of gp130 with the OSM-specific b receptor (OSMR) subunit, resulting in activation of the JAK/STAT and MAP kinase signalling pathways (Heinrich et al, 2003).”
BackgroundInterleukin-11 expression: its significance in eutopic and ectopic human implantation
von Rango, U., Alfer, J., Kertschanska, S., Kemp, B., Müller‐Newen, G., Heinrich, P. C., Beier, H. M., & Classen-Linke, I. (2004) · Molecular Human Reproduction · doi:10.1093/molehr/gah107 · Cited by 53
“Besides IL-6 itself and IL-11, ciliary neurotrophic factor (CNTF), cardiotrophin (CT-1), oncostatin M (OSM), leukaemia inhibitory factor (LIF) and cardiotrophin-like cytokine (CLC) (Elson et al., 2000) belong to this group of cytokines (Heinrich et al., 1998, 2003).”
BackgroundSelf-citationKanthasamy, A., Jin, H., Charli, A., Anantharam, V., & Kanthasamy, A. G. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.01.001 · Cited by 57
“STAT proteins, importantly STAT3, are latent cytoplasmic transcription factors that becomeactivated following tyrosine phosphorylation by members of the JAK family, eventually leading to transcriptional activation (Heinrich et al., 2003; Levy & Darnell Jr, 2002).”
Płóciennikowska, A., Frankish, J., Moraes, T. D. F. S., Prete, D. D., Kahnt, F., Acuna, C., Ślęzak, M., Binder, M., & Bartenschlager, R. F. W. (2021) · Journal of Virology · doi:10.1128/jvi.01050-20 · Cited by 52
Woolson, H. D., Thomson, V. S., Rutherford, C. L., Yarwood, S. J., & Palmer, T. M. (2009) · Cellular Signalling · doi:10.1016/j.cellsig.2009.07.009 · Cited by 52
Ross, J. S., Hu, W. M., Rosen, B. P., Snider, A. J., Obeid, L. M., & Cowart, L. A. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.477786 · Cited by 58
“Classical signaling of IL-6 occurs through the IL-6 receptor and results in the transcription of Socs3 in both muscle and adipose (64).”
BackgroundLu, Z., Wang, J., Zheng, T., Liang, Y., Yin, D., Song, R., Pei, T., Pan, S., Jiang, H., & Liu, L. (2014) · BMC Cancer · doi:10.1186/1471-2407-14-783 · Cited by 52
“STAT proteins comprise a seven member family of latent cytoplasmic transcription factors [10,33].”
BackgroundWhite, J. P., Reecy, J. M., Washington, T. A., Sato, S., Le, M. E., Davis, J. M., Wilson, L. B., & Carson, J. A. (2009) · Acta Physiologica · doi:10.1111/j.1748-1716.2009.02029.x · Cited by 53
“phosphorylation, which recruits and phosphorylates STAT proteins (Heinrich et al. 2003).”
BackgroundInfluentialRussell, M. A., Cooper, A. C., Dhayal, S., & Morgan, N. G. (2013) · Islets · doi:10.4161/isl.24249 · Cited by 52
Endogenous leukemia inhibitory factor attenuates endotoxin response
Weber, M. A., Schnyder‐Candrian, S., Schnyder, B., Quesniaux, V. F. J., Poli, V., Stewart, C. L., & Ryffel, B. (2005) · Laboratory Investigation · doi:10.1038/labinvest.3700216 · Cited by 52
CP690,550 inhibits oncostatin M-induced JAK/STAT signaling pathway in rheumatoid synoviocytes
Migita, K., Komori, A., Torigoshi, T., Maeda, Y., Izumi, Y., Jiuchi, Y., Miyashita, T., Nakamura, M., Motokawa, S., & Ishibashi, H. (2011) · Arthritis Research & Therapy · doi:10.1186/ar3333 · Cited by 53
“OSM is known to activate the JAK/STAT signaling cascade in other systems [17], but this has not been properly elucidated in rheumatoid synoviocytes.”
BackgroundHosur, V., & Loring, R. H. (2010) · Molecular Pharmacology · doi:10.1124/mol.110.066381 · Cited by 52
Pritchard, M. T., Cohen, J. I., Roychowdhury, S., Pratt, B. T., & Nagy, L. E. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.04.017 · Cited by 54
“While glycoprotein (gp)130, the receptor chain shared by all IL-6 family members [11], and IL-6Ra (gp80), the IL-6-specific receptor component [11], were increased over baseline 18 h after CCl4 exposure, they did not differ between wild-type and egr-1 / mice (Fig.”
Moidunny, S., Vinet, J., Wesseling, E. M., Bijzet, J., Shieh, C., van Ijzendoorn, S. C., Bezzi, P., Boddeke, H. W. G. M., & Biber, K. P. H. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-198 · Cited by 52
“Abbreviations A2B KO: A2B receptor knock-out; BFA: Brefeldin A; bp: base pairs; ChAT: choline acetyltransferase; CNS: central nervous system; CNTF: ciliary neurotrophic factor; CT-1: cardiotrophin-1; DMEM: Dulbecco’s modified Eagle’s medium; DMSO: dimethyl sulfoxide; EDTA: ethylenediaminetetraacetic acid; EPAC: Exchan…”
BackgroundInfluentialPoplutz, M. K., Weßels, I., Rink, L., & Uciechowski, P. (2014) · Immunobiology · doi:10.1016/j.imbio.2014.03.016 · Cited by 52
“1999a, 1999b; Heinrich et al. 2003; Nile et al. 2008; Dandrea t al.”
Emerging strategies for cancer immunoprevention
Roeser, J. C., Leach, S. D., & McAllister, F. E. (2015) · Oncogene · doi:10.1038/onc.2015.98 · Cited by 53
“Interleukin-6: The complex of IL-6 and IL-6R does not lead to signaling but instead associates with the protein gp130 inducing its dimerization and starting intracellular signaling via the JAK/STAT and the Ras-Raf-MAPK signaling pathways [32].”
BackgroundВиткина, Т. И., Yan’kova, V. I., Gvozdenko, T. A., Kuznetsov, V. L., Krasnikov, D. V., Nazarenko, A. V., Чайка, В., Смагин, С. В., Tsatsakis, A. M., Engin, A. B., et al. (2015) · Food and Chemical Toxicology · doi:10.1016/j.fct.2015.11.023 · Cited by 54
“Up-regulation of anti-apoptotic pathway in the presence JAK, which phosphorylate STAT3, thus modulating the expression of a broad spectrum of downstream target genes (Heinrich et al., 2003).”
BackgroundNasrolahi, A., Mahmoudi, J., Akbarzadeh, A., Karimipour, M., Sadigh‐Eteghad, S., Salehi, R., & Farhoudi, M. (2018) · Reviews in the Neurosciences · doi:10.1515/revneuro-2017-0040 · Cited by 52
Natural Salicylates and Their Roles in Human Health
Yeasmin, F., & Choi, H. W. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239049 · Cited by 56
Updating interleukin‐6 classic‐ and trans‐signaling
Scheller, J., Grötzinger, J., & Rose‐John, S. (2006) · Signal Transduction · doi:10.1002/sita.200600086 · Cited by 53
Alternative Signaling Pathways Regulating Type I Interferon-Induced Apoptosis
Tamm, K. P., Panaretakis, T., & Grandér, D. (2005) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2005.25.799 · Cited by 51
Expression of Reg/PAP family members during motor nerve regeneration in rat
Namikawa, K., Fukushima, M., Murakami, K., Suzuki, A., Takasawa, S., Okamoto, H., & Kiyama, H. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.04.105 · Cited by 52
Underhill-Day, N., & Heath, J. K. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-1766 · Cited by 52
“Activation of both the JAK/STAT and MAPK pathways by gp130 cytokines has been well defined as a mechanism of signal transduction (6).”
BackgroundMethodThe weight of interleukin-6 in B cell-related autoimmune disorders
Youinou, P., & Jamin, C. (2009) · Journal of Autoimmunity · doi:10.1016/j.jaut.2009.02.013 · Cited by 52
Lee, S., Buhimschi, I. A., Dulay, A. T., et al. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003587 · Cited by 52
“genes via trans-signaling pathway is controlled by an inhibitory mechanism (6).”
InfluentialInsights Into Host Cell Cytokines in Chlamydia Infection
Xiang, W., Yu, N., Lei, A., Li, X., Tan, S., Huang, L., & Zhou, Z. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.639834 · Cited by 51
“IL-6 promotes the terminal differentiation of B cells (90) and T cell survival (91) and helps T cells to overcome suppression by Tregs (92); its most noticeable role is in the defense against infection (90, 93).”
BackgroundBCL6 , a key oncogene, in the placenta, pre-eclampsia and endometriosis
Louwen, F., Kreis, N., Ritter, A., Friemel, A., Solbach, C., & Yuan, J. (2022) · Human Reproduction Update · doi:10.1093/humupd/dmac027 · Cited by 53
“.. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. ..Kim BG, Yoo JY, Kim TH, Shin JH, Langenheim JF, Ferguson SD…”
BackgroundInfluentialIL-6 is produced by adipose-derived stromal cells and promotes osteogenesis
Huh, J.-E., & Lee, S. Y. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.06.025 · Cited by 52
“This leads to activation of STAT3 by tyrosine phosphorylation and then to STAT3 dimerization [19].”
BackgroundRegulation Generation: The Suppressive Functions of Human Regulatory T Cells
Goodman, W. A., Cooper, K. D., & McCormick, T. S. (2012) · Critical Reviews in Immunology · doi:10.1615/critrevimmunol.v32.i1.40 · Cited by 52
Zorina, Y., Iyengar, R., & Bromberg, K. D. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.049841 · Cited by 50
Martin, M., & Herceg, Z. (2012) · Genome Medicine · doi:10.1186/gm307 · Cited by 51
“IL6 binding activates the phosphorylation of a JAK (mostly JAK2), which in turn will phosphorylate STAT3 on amino acid Y705 [53].”
BackgroundSOCS2 correlates with malignancy and exerts growth-promoting effects in prostate cancer
Hoefer, J., Kern, J., Ofer, P., Eder, I. E., Schäfer, G., Dietrich, D., Kristiansen, G., Geley, S., Rainer, J., Gunsilius, E., et al. (2013) · Endocrine Related Cancer · doi:10.1530/erc-13-0446 · Cited by 52
“…altered expression of endogenous key regulators such as protein inhibitors of activated STAT (PIAS), Src-homology 2 (SH2)-containing protein tyrosine phosphatases, and suppressors of cytokine signaling (SOCS; Larsen & Ropke 2002, Heinrich et al. 2003, sed under a Creative Commons nported License.”
BackgroundOncostatin M differentially regulates CXC chemokines in mouse cardiac fibroblasts
Lafontant, P. J., Burns, A. R., Donnachie, E., Haudek, S. B., Smith, C. W., & Entman, M. L. (2006) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00322.2005 · Cited by 51
“To understand OSM regulation of CXC chemokines in mCFs, we studied the main signaling pathways activated by OSM (20).”
BackgroundDay, J. S., O'Neill, E., Cawley, C. L., Aretz, N. K., Kilroy, D., Gibney, S. M., Harkin, A., & Connor, T. J. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.09.027 · Cited by 51
Protective effects of plant-derived flavonoids on hepatic injury
Wan, L., & Jiang, J. (2018) · Journal of Functional Foods · doi:10.1016/j.jff.2018.03.015 · Cited by 52
Slaets, H., Dumont, D., Vanderlocht, J., Noben, J., Leprince, P., Robben, J., Hendriks, J. J. A., Stinissen, P., & Hellings, N. (2008) · PROTEOMICS · doi:10.1002/pmic.200700641 · Cited by 51
“At least three antiapoptotic pathways can be activated by LIF: the phosphatidylinositol 3 (PI3) kinase pathway, the janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway and the extracellular signal regulated kinase (ERK1/2) pathway [11, 16, 17].”
BackgroundNg, G., Winder, D. M., Muralidhar, B., et al. (2007) · The Journal of Pathology · doi:10.1002/path.2184 · Cited by 51
“In order to understand better the biological actions of OSMR and hence its contribution towards the malignant phenotype in cervical SCC, we next investigated which signalling pathways known to be downstream of OSMR [23] were activated by OSM in CaSki and SW756 cells.”
BackgroundOncostatin M is a potent inducer of hepcidin, the iron regulatory hormone
Chung, B., Verdier, F., Matak, P., Deschemin, J., Mayeux, P., & Vaulont, S. (2010) · The FASEB Journal · doi:10.1096/fj.09-152561 · Cited by 51
“OsM is an inflammatory cytokine member of the IL-6-related cytokine family that includes IL-6, IL-11, ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), cardiotrophinlike cytokine (CLC), and neuropoietin (NPN) (54).”
BackgroundSuppressor of cytokine signaling 4 (SOCS4): Moderator of ovarian primordial follicle activation
Sutherland, J. M., Keightley, R., Nixon, B., Roman, S. D., Robker, R. L., Russell, D. L., & McLaughlin, E. A. (2011) · Journal of Cellular Physiology · doi:10.1002/jcp.22837 · Cited by 51
“Further to this we propose that CLC protein acts similarly to LIF in an autocrine manner by binding to the LIF and gp130 receptors (Heinrich et al., 2003; Katoh, 2007), triggering a phosphorylation cascade resulting primordial follicle activation and the tyrosine phosphorylation of STAT3 and…”
BackgroundMalaval, L., Liu, F., Vernallis, A. B., et al. (2005) · Journal of Cellular Physiology · doi:10.1002/jcp.20312 · Cited by 51
“Also, while there is evidence that gp130/LIFR and gp130/ OSMR receptor complexes activate distinct signaling networks (Hermanns et al., 2000; Heinrich et al., 2003), the biological consequences of this in specific tissues/ organs are only beginning to be explored.”
BackgroundMitochondrial fat oxidation is essential for lipid-induced inflammation in skeletal muscle in mice
Warfel, J. D., Bermudez, E. M., Mendoza, T. M., Ghosh, S., Zhang, J., Elks, C. M., Mynatt, R., & Vandanmagsar, B. (2016) · Scientific Reports · doi:10.1038/srep37941 · Cited by 50
“In addition to phosphorylation at Ser 727, STAT3 is activated through phosphorylation at Tyr 705 in response to various cytokines including IFNs (interferons), IL5 and IL6 (interleukins 5 and 6) 37–39 .”
Inflammatory Microenvironment Accelerates Bone Marrow Mesenchymal Stem Cell Aging
Peng, X., Zhou, X. H., Yin, Y., Luo, B., Liu, Y., & Yang, C. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.870324 · Cited by 50
Thyroid hormones act as modulators of inflammation through their nuclear receptors
Lasa, M., & Contreras‐Jurado, C. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.937099 · Cited by 56
“Alternatively, STAT proteins can physically interact with other proteins, such as components of the NF-kB signaling cascade (41), or can be transcriptionally activated by other proteins, such as p38MAPK (42).”
BackgroundXue, W., Cojocaru, R. I., Dudley, V. J., Brooks, M., Swaroop, A., & Sarthy, V. P. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020326 · Cited by 50
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“They activate target genes involved in differentiation, survival, apoptosis and proliferation (1).”
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“The HFD exposure induced a significant increase in the p-AMPK/AMPK ratio in WT (P 0.001) and IL-6−/− mice (P 0.05) compared with the respective STD-fed groups (Fig.”
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“Deregulation of IL-6-type cytokine signaling contributes to the onset and maintenance of several diseases, exerting its action through the activation of the JAKISTAT (Janus kinase/signal transducer and activator of transcription) and MAPK (mitogen activated protein kinase) cascades (22).”
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“Overproduction of the IL-6 family of cytokines, aberrant activation of their receptors or receptorassociated tyrosine kinases, or epigenetic alterations or mutations in genes encoding negative regulators of STAT3 can bring about persistent STAT3 activation [44–46].”
BackgroundIL-27: a double agent in the IL-6 family
Jones, G. W., Hill, D. G., Figueras, A. C., & Jones, S. A. (2018) · Clinical & Experimental Immunology · doi:10.1111/cei.13116 · Cited by 48
“Interleukin-27 is however the only member of the IL-6-related cytokine family to predominantly signal via STAT1 instead of STAT3 [1, 3].”
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“…component, gp130, acts in association with ligand-specific receptors for members of the interleukin-6 (IL-6) cytokine family, including IL-6, IL-11, LIF, ciliary neurotrophic factor (CNTF), oncostatin-M (OSM), cardiotrophin-1 (CT-1), and cardiotrophin-like cytokine (CLC) (Heinrich et al, 2003).”
BackgroundInfluentialTron, K., Samoylenko, A., Musikowski, G., Kobe, F., Immenschuh, S., Schaper, F., Ramadori, G. P., & Kietzmann, T. (2006) · Journal of Hepatology · doi:10.1016/j.jhep.2005.12.019 · Cited by 51
“In addition to the Jak/STATpathway, IL-6 alsomodulates the activities of several members of the mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) cascades [15].”
BackgroundInfluentialSelf-citationInvolvement of Epithelial-Mesenchymal Transition (EMT) in Autoimmune Diseases
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“inflammation, hematopoiesis, and immune responses (1, 2).”
BackgroundTPO-independent megakaryocytopoiesis
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“[39] Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G,”
BackgroundThe enigma of the role of Protein inhibitor of Activated STAT3 (PIAS3) in the immune response
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How Do Cytokines Trigger Genomic Instability?
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“As a result, RGC death is markedly delayed, and lengthy axons are regenerated into the inhibitory environment of a crushed optic nerve (Fischer et al. 2000, 2001; Leon et al. 2000).”
BackgroundFunction of the chondrocyte PI-3 kinase-Akt signaling pathway is stimulus dependent
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“IL-1β is well known to activate MAP kinase signaling, and OSM can activate the JAKSTAT pathway (11, 12).”
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“This subfamily includes ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), interleukin-6 (IL-6), interleukin-11 (IL-11), oncostatin M (OSM), cardiotrophin-1 (CT-1) and so on (Heinrich et al. 2003; Murakami et al. 2004).”
BackgroundMouse models for gastric cancer: Matching models to biological questions
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“Of note, SOCS, the natural terminators of cytokine signaling, are involved via regulating the phosphorylation of downstream molecules (76).”
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“OSMR signaling initiates the JAK/STAT, mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase/AKT pathways [13, 14], as well as the stress-activated MAPK p38 and JNK pathways [15].”
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“JAK2 can activate a series of downstream signaling pathways, including the STAT cascade (39,40).”
BackgroundExtracellular signal-dependent nuclear import of STAT3 is mediated by various importin αs
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“Induction of COX-2 precedes IL-6 gene expression (16).”
IL-6 in the Ecosystem of Head and Neck Cancer: Possible Therapeutic Perspectives
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“They are consequently phosphorylated within their tyrosine sites (STAT1: Y701, STAT3: Y705), dimerized and translocated into the nucleus [22,26,27].”
BackgroundSingle‐cell transcriptomics reveals a senescence‐associated IL‐6/CCR6 axis driving radiodermatitis
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“Dysregulation of IL-6-type cytokine signalling contributes to the onset and maintenance of several chronic diseases.(22) Acute moderate and strenuous intensity(23) EX are associated with acute-phase response, with prolonged effects decreasing after EX, suggesting cytokine inhibitors and anti-inflammatory cytokines may…”
Background
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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