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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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Eskilsson, A., Mirrasekhian, E., Dufour, S., Schwaninger, M., Engblom, D., & Blomqvist, A. G. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.3520-14.2014 · Cited by 142
“Thus, although the present study shows that deletion in the brain endothelium of STAT3, on which IL-6 signaling is dependent (Heinrich et al., 2003), resulted in attenuated fever, activation of this signaling pathway alone is not sufficient for eliciting Cox-2 induction and prostaglandin synthesis, but also requires t…”
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Treg versus Th17 lymphocyte lineages are cross-regulated by LIF versus IL-6
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“(30), we investigated whether curcumin might influence the JAK/STAT3 pathway and whether blockade of this pathway may account for the antiglioma activity of curcumin.”
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Distinct Effects of IL-6 Classic and Trans -Signaling in Bone Fracture Healing
Prystaz, K., Kaiser, K., Kovtun, A., Haffner-Luntzer, M., Fischer, V., Rapp, A. E., Liedert, A., Strauss, G., Waetzig, G. H., Rose-John, S., et al. (2018) · The American Journal of Pathology · doi:10.1016/j.ajpath.2017.10.011 · Cited by 142
“This leads to intracellular signal transduction, involving the JAK/STAT (Janus kinase/signal transducers and activators of transcription), MAPK (mitogen-activated protein kinase), and PI3K (phosphoinositide 3-kinase) pathways (23).”
BackgroundSTAT3: An Emerging Therapeutic Target for Hepatocellular Carcinoma
Lee, C., & Cheung, S. (2019) · Cancers · doi:10.3390/cancers11111646 · Cited by 148
“pS727 is required for maximal activation although pY705 plays a key activating role [24,25].”
BackgroundZhong, Q., Fang, Y., Lai, Q., Wang, S., He, C., Li, A., Liu, S., & Yan, Q. (2020) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-020-01637-4 · Cited by 141
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Anti-Inflammatory and Immunosuppressive Effects of the A2AAdenosine Receptor
Milne, G. R., & Palmer, T. M. (2011) · The Scientific World JOURNAL · doi:10.1100/tsw.2011.22 · Cited by 139
“They mediate their inhibitory effects in part by binding to phosphorylated tyrosine residues on activated receptors and interacting with receptor-associated JAKs via the KIR[72].”
BackgroundInfluentialScuto, A., Krejčı́, P., Popplewell, L. L., Wu, J., wang, Y., Kujawski, M., Kowolik, C. M., Xin, H., Chen, L., Wang, Y., et al. (2010) · Leukemia · doi:10.1038/leu.2010.289 · Cited by 140
Arterial Hypertension and Interleukins: Potential Therapeutic Target or Future Diagnostic Marker?
Tănase, D. M., Gosav, E. M., Radu, S., Ouatu, A., Rezuș, C., Ciocoiu, M., Costea, C. F., & Floria, M. (2019) · International Journal of Hypertension · doi:10.1155/2019/3159283 · Cited by 141
“There are 3 types of Th cells: Th1 cells which produce interferon-g (IFN-g), Th2 cells which produce IL-4 and IL5; and IL-13, a third type of Th cells that secrete IL-17A, IL17F, and IL-22 [129, 130].”
BackgroundGarg, M., Shanmugam, M. K., Bhardwaj, V., Goel, A., Gupta, R., Sharma, A., Baligar, P., Kumar, A. P., Goh, B. C., Wang, L., et al. (2020) · Medicinal Research Reviews · doi:10.1002/med.21761 · Cited by 143
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“IL-6–induced biological responses are mediated by the membranebound IL-6R (IL-6Ra; CD126) (7, 9, 10).”
BackgroundInfluentialPARP1 Suppresses the Transcription of PD-L1 by Poly(ADP-Ribosyl)ating STAT3
Ding, L., Chen, X., Xu, X., Qian, Y., Liang, G., Yao, F., Yao, Z., Wu, H., Zhang, J., He, Q., et al. (2018) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-18-0071 · Cited by 138
“Phosphorylated STAT3 monomers form homo- or heterodimers and translocate to the nucleus where they bind to specific sequences in the promoters of target genes to regulate gene transcription (47).”
BackgroundPüschel, G. P., Klauder, J., & Henkel, J. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11154358 · Cited by 156
Interleukin-11 Potentiates Oligodendrocyte Survival and Maturation, and Myelin Formation
Zhang, Y., Taveggia, C., Melendez‐Vasquez, C. V., Einheber, S., Raine, C. S., Salzer, J. L., Brosnan, C. F., & John, G. R. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.2289-06.2006 · Cited by 141
“The gp130 family is of increasing interest in immunology and neurobiology because of the ability of specific members to function as modulators of proliferation, differentiation, and/or survival for multiple cell lineages (Heinrich et al., 2003).”
BackgroundSauer, H., & Wartenberg, M. (2005) · Antioxidants and Redox Signaling · doi:10.1089/ars.2005.7.1423 · Cited by 138
“…accompanied by and dependent on the production of ROS, which suggested that modulation of VE cadherin function directly affected the efficiency of reorganization of the endothelial actin cytoskeleton and by modulating the integrity of the bone marrow endothelium through the production of ROS (115).”
Tohda, C., Nakayama, N., Hatanaka, F., et al. (2006) · Evidence-based Complementary and Alternative Medicine · doi:10.1093/ecam/nel008 · Cited by 138
“At the same time, increased IL-1b and TNF-a in inflammation upregulate the IL-6 expression (20), and IL-6 stimulation in the liver induces the translocation of activated STAT3 molecules to nuclei (21,22).”
BackgroundIL-6: The Link Between Inflammation, Immunity and Breast Cancer
Chen, J., Wei, Y., Yang, W., Huang, Q., Chen, Y., Zeng, K., & Chen, J. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.903800 · Cited by 151
Hu, L., Liu, R., & Zhang, L. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.109095 · Cited by 137
IL-6 Modulates Alpha-Smooth Muscle Actin Expression in Dermal Fibroblasts from IL-6-Deficient Mice
Gallucci, R. M., Lee, E. G., & Tomasek, J. J. (2006) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5700109 · Cited by 138
“This is not surprising as JAK1 is activated preferentially by the IL-6R and responsible for the majority of its signaling activity (Heinrich et al., 2003).”
BackgroundInfluentialJee, S., Chu, C., Chiu, H.-C., Huang, Y., Tsai, W.-L., Liao, Y., & Kuo, M. (2004) · Journal of Investigative Dermatology · doi:10.1111/j.0022-202x.2004.23497.x · Cited by 137
“…pathways are involved in IL-6 induced upregulation of bFGF Three major signaling pathways including the JAK/STAT3 pathway, PI3Kinase/Akt pathway, and mitogen-activated protein kinase (MAPK) pathway (Heinrich et al, 2003) have been reported to be involved in the IL-6-mediated cellular functions.”
BackgroundInterleukin-6 and interleukin-11: same same but different
Garbers, C., & Scheller, J. (2013) · Biological Chemistry · doi:10.1515/hsz-2013-0166 · Cited by 134
The role of epigenetics in the biology of multiple myeloma
Dimopoulos, K., Gimsing, P., & Grønbæk, K. (2014) · Blood Cancer Journal · doi:10.1038/bcj.2014.29 · Cited by 133
Cytokines in head and neck cancer
Pries, R., & Wollenberg, B. (2006) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2006.02.001 · Cited by 135
“in distinct cellular processes like cell differentiation, the production of acute phase proteins in the liver, the proliferation of B-lymphocytes, and the production of neutrophils [56].”
BackgroundInflammation, ageing and cancer
Vasto, S., Carruba, G., Lio, D., Colonna‐Romano, G., Bona, D. D., Candore, G., & Caruso, C. (2008) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2008.06.003 · Cited by 134
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The role of the interleukin (IL)-6/IL-6 receptor axis in cancer
Taher, M. Y., Davies, D. M., & Maher, J. F. (2018) · Biochemical Society Transactions · doi:10.1042/bst20180136 · Cited by 138
STAT3 signaling after traumatic brain injury
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Hormone Replacement Therapy and Physical Function in Healthy Older Men. Time to Talk Hormones?
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“IL-6 does not only lead to the activation of the STAT signalling, but also to the induction of the MAPK cascade [44].”
Johnson, E. C., Doser, T. A., Cepurna, W. O., Dyck, J. A., Jia, L., Guo, Y., Lambert, W. S., & Morrison, J. C. (2010) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.10-5317 · Cited by 130
The Membrane-Associated MARCH E3 Ligase Family: Emerging Roles in Immune Regulation
Lin, H., Li, S., & Shu, H.-B. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01751 · Cited by 124
“In response to ConA, CD4 T lymphocytes release LIF, which plays important roles in immune tolerance (125, 126).”
BackgroundTam, L., McGlynn, L. M., Traynor, P., Mukherjee, R., Bartlett, J. M. S., & Edwards, J. (2007) · British Journal of Cancer · doi:10.1038/sj.bjc.6603871 · Cited by 131
Paradigm shifts in the cell biology of STAT signaling
Sehgal, P. B. (2008) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2008.07.003 · Cited by 135
Blecharz-Lang, K. G., Wagner, J., Fries, A., Nieminen-Kelhä, M., Rösner, J., Schneider, U. C., & Vajkoczy, P. (2018) · Translational Stroke Research · doi:10.1007/s12975-018-0614-2 · Cited by 130
“The dimerization of both receptors in response to IL6 binding is yet essential for the activation of intracellular JAK/signal transducer and activator of transcription (JAK/STAT) signaling pathway [17].”
BackgroundCosenza, M., Sacchi, S., & Pozzi, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147652 · Cited by 134
Miao, T., Wu, D., Zhang, Y., Bo, X., Subang, M. C., Wang, P., & Richardson, P. M. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.2160-06.2006 · Cited by 131
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“these cytokines is governed by the expression patterns of different a-subunit receptors, CNTFR for CLCF1, and IL-6R for IL-6, which can be activated by each cytokine independently (50).”
BackgroundInfluentialSiveen, K. S., Prabhu, K. S., Achkar, I. W., Kuttikrishnan, S., Shyam, S., Khan, A. Q., Merhi, M., Dermime, S., & Shahab Uddin, M. S. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0788-y · Cited by 137
“2m) is a diterpenoid isolated from Rabdosia rubescens inhibited lyn and abl levels along with downstream target Akt/mTOR, Raf/MEK/ERK and STAT5 in Ph +ALL cell line and primary specimens from Ph +ALL patients.”
BackgroundInfluentialInfluence of interleukin polymorphisms on development of gastric cancer and peptic ulcer
Sugimoto, M. (2010) · World Journal of Gastroenterology · doi:10.3748/wjg.v16.i10.1188 · Cited by 128
Reeves, M. B., & Compton, T. (2011) · Journal of Virology · doi:10.1128/jvi.05878-11 · Cited by 127
“The best-characterized pathway is JAK/STAT signaling, which promotes the activation of a number of STAT-responsive genes, including the acutephase response proteins (14).”
BackgroundCell-surface heparan sulfate proteoglycans as multifunctional integrators of signaling in cancer
Hassan, N., Greve, B., Espinoza‐Sánchez, N. A., & Götte, M. (2020) · Cellular Signalling · doi:10.1016/j.cellsig.2020.109822 · Cited by 129
Jung, J. E., Kim, G. S., & Chan, P. H. (2011) · Stroke · doi:10.1161/strokeaha.111.626648 · Cited by 127
Ataie-Kachoie, P., Pourgholami, M., & Morris, D. (2013) · Cytokine & growth factor reviews · doi:10.1016/j.cytogfr.2012.09.001 · Cited by 123
“After phosphorylation, STAT3 forms a dimer which is then translocated to the nucleus to transmit signals from the cell membrane to the nucleus [13].”
BackgroundCardiovascular Biology of Interleukin-6
Abeywardena, M. Y., Leifert, W. R., Warnes, K., Varghese, J. N., & Head, R. J. (2009) · Current Pharmaceutical Design · doi:10.2174/138161209788186290 · Cited by 128
“Abbreviations: Janus kinase (JAK), signal transducer and activator of transcription (STAT), suppressor of cytokine signalling (SOCS), tyrosine kinase (Tyrk). rearrangement of the receptor with a phosphorylation of the associated JAKs.”
BackgroundJiang, M., Chen, J., Zhang, W., Zhang, R., Ye, Y., Liu, P., Yu, W., Wei, F., Ren, X., & Yu, J. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01840 · Cited by 129
“Under physiological conditions, IL-6 stimulates the expression of SOCS3 and inhibits phosphorylation of STAT proteins (20).”
BackgroundThe biology and therapeutic potential of interleukin 27
Batten, M., & Ghilardi, N. (2007) · Journal of Molecular Medicine · doi:10.1007/s00109-007-0164-7 · Cited by 130
“SOCS3 is known to suppress IL-6 signaling by binding to gp130 at phosphorylated tyrosine residues and, thus, preventing JAK association and STAT-3 activation [68].”
BackgroundLentzsch, S., Chatterjee, M., Gries, M., Bommert, K., Gollasch, H., Dörken, B., & Bargou, R. C. (2004) · Leukemia · doi:10.1038/sj.leu.2403486 · Cited by 124
The Role of Interleukin-6 Family Members in Cardiovascular Diseases
Feng, Y., Ye, D., Wang, Z., Pan, H., Lu, X., Wang, M., Xu, Y. Q., Yu, J., Zhang, J., Zhao, M., et al. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.818890 · Cited by 139
Fischer, P., & Hilfiker‐Kleiner, D. (2008) · British Journal of Pharmacology · doi:10.1038/bjp.2008.1 · Cited by 126
“Activation of gp130 in the heart by IL-6 type cytokines occurs during embryogenesis, in response to inflammation, pressure overload and ischaemic injury thereby inducing signalling via three major pathways: (1) the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, (2) the Ras/mitogen-…”
BackgroundInfluentialNatsu, K., Ochi, M., Mochizuki, Y., Hachisuka, H., Yanada, S., & Yasunaga, Y. (2004) · Tissue Engineering · doi:10.1089/ten.2004.10.1093 · Cited by 126
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“To substantiate the IL-6R activity in the salivary gland, we utilized the induction of STAT3 phosphorylation, one of three main IL-6 signal transduction pathways (39), as a surrogate marker for IL-6/IL-6R signaling following infusion of IL-6 into the salivary gland ducts.”
Nardone, S., & Elliott, E. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00329 · Cited by 138
“Two of the main signal transduction pathways that are activated by cytokines are JAK/STAT and MAPK/ERK signaling pathways (Heinrich et al., 2003).”
BackgroundThe role of leptin in innate and adaptive immune responses.
Bernotienė, E., Palmer, G., & Gabay, C. (2006) · Arthritis Research & Therapy · doi:10.1186/ar2004 · Cited by 134
Flowers, L. O., Subramaniam, P. S., & Johnson, H. M. (2005) · Oncogene · doi:10.1038/sj.onc.1208437 · Cited by 125
Morris, M. K., Sáez-Rodríguez, J., Clarke, D. C., Sorger, P. K., & Lauffenburger, D. A. (2011) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1001099 · Cited by 123
“This phosphorylation can lead to PI3K/Akt pathway activation through interactions with Gab-1 or IRS1 or Ras/MEK/ERK pathway activation through Grb2 or Gab1 [54].”
BackgroundMethodStrippoli, R., Carvello, F., Scianaro, R., Pasquale, L. D., Vivarelli, M., Petrini, S., Bracci‐Laudiero, L., & Benedetti, F. D. (2011) · Arthritis & Rheumatism · doi:10.1002/art.33496 · Cited by 123
“STAT-3 is tyrosine phosphorylated by the JAK kinases, which dimerizes and translocates to the nucleus where it exerts its transcription activity (9).”
BackgroundJak-Stat Signaling Induced by Interleukin-6 Family Cytokines in Hepatocellular Carcinoma
Lokau, J., Schoeder, V., Haybaeck, J., & Garbers, C. (2019) · Cancers · doi:10.3390/cancers11111704 · Cited by 127
“Phosphorylation of STATs results in dissociation from the receptor and reorientation in active homo- or heterodimers, which regulate the transcription of target genes [56,60,61] (Figure 2).”
BackgroundKim, E., Kim, H., Jedrychowski, M. P., Bakiasi, G., Park, J., Kruskop, J. M., Choi, Y., Kwak, S. S., Quinti, L., Kim, D. Y., et al. (2023) · Neuron · doi:10.1016/j.neuron.2023.08.012 · Cited by 141
Waiboci, L. W., Ahmed, C. M. I., Mujtaba, M. G., Flowers, L. O., Martin, J. P., Haider, M. I., & Johnson, H. M. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.8.5058 · Cited by 122
Chatterjee, M., Stühmer, T., Herrmann, P., Bommert, K., Dörken, B., & Bargou, R. C. (2004) · Blood · doi:10.1182/blood-2004-04-1670 · Cited by 124
“Binding of IL-6 to IL-6Rα induces recruitment of IL-6Rβ subunits and initiates at least two intracellular signaling pathways: the Janus kinase/Signal transducer and activator of transcription 3 (JAK/STAT3), and the Ras/Mitogenactivated protein kinase (MAPK) pathway.(11) IL-6-mediated induction of the Ras/MAPK pathway…”
BackgroundArora, L., Kumar, A. P., Arfuso, F., Chng, W. J., & Sethi, G. (2018) · Cancers · doi:10.3390/cancers10090327 · Cited by 124
Role of IL-6 in dendritic cell functions
Xu, Y.-D., Cheng, M., Shang, P.-P., & Yang, Y.-Q. (2021) · Journal of Leukocyte Biology · doi:10.1002/jlb.3mr0621-616rr · Cited by 130
Liu, L., Leung, K., Chan, D. S.-H., Wang, Y.-T., Ma, D., & Leung, C.-H. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.250 · Cited by 123
“On the other hand, the C terminus contains a conserved tyrosine (Tyr705) residue that is essential for STAT3 activation.(15) In the classical STAT3 activation pathway, growth factors and cytokines induce the tyrosine kinase activities of JAK or Src receptors, resulting in specific tyrosine phosphorylation of receptor…”
BackgroundKim, B. G., Yoo, J., Kim, T. H., Shin, J., Langenheim, J. F., Ferguson, S. D., Fazleabas, A. T., Young, S. L., Lessey, B. A., & Jeong, J. (2015) · Human Reproduction · doi:10.1093/humrep/dev050 · Cited by 123
“Interleukin-6 (IL-6) is a well-characterized pro-inflammatory cytokine previously implicated with this disease (Heinrich et al., 2003).”
BackgroundDifferential cytokine regulation by NF-κB and AP-1 in Jurkat T-cells
Khalaf, H., Jaß, J., & Olsson, P. (2010) · BMC Immunology · doi:10.1186/1471-2172-11-26 · Cited by 122
“IL-6 is a cytokine that possesses both pro- and anti-inflammatory characteristics and that plays a key role in haematopoiesis and acute-phase responses [24,25].”
PRL‐3 phosphatase and cancer metastasis
Al-Aidaroos, A. Q., & Zeng, Q. (2010) · Journal of Cellular Biochemistry · doi:10.1002/jcb.22913 · Cited by 121
“Although the functional relevance of these transcription factors on PRL-3 expression have not directly been reported, a recent study showed that stimulation of myeloma cells with interleukin-6, a cytokine which promotes STAT3 transcriptional activity [Heinrich et al., 2003], could potently induce a 2.”
BackgroundInfluentialCoordination of Immune-Stroma Crosstalk by IL-6 Family Cytokines
West, N. R. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01093 · Cited by 125
“For example, unlike gp130, OSMR efficiently recruits the adapter protein SHC, allowing OSM to drive more potent activation of the MAPK pathway than IL-6, which signals via SHP-2 bound to gp130 (35, 36).”
BackgroundInfluentialStanke, M., Duong, C. V., Pape, M., Geißen, M., Burbach, G. J., Deller, T., Gascan, H., Parlato, R., Schütz, G., & Rohrer, H. (2005) · Development · doi:10.1242/dev.02189 · Cited by 123
“…can be explained by their common mechanism of action, activating receptor complexes that share the signaling receptor subunit gp130 (IL6ST – Mouse Genome Informatics), leading to the alternative term gp130 cytokines for IL6 cytokine family members (Taga and Kishimoto, 1997; Heinrich et al., 2003).”
The role of IL-11 in immunity and cancer
Xu, D. H., Zhu, Z., Wakefield, M. R., Xiao, H., Bai, Q., & Fang, Y. (2016) · Cancer Letters · doi:10.1016/j.canlet.2016.01.004 · Cited by 134
Role of Inflammation and Cytokines in Peripheral Nerve Regeneration
Dubový, P., Jančálek, R., & Kubek, T. (2013) · International review of neurobiology · doi:10.1016/b978-0-12-410499-0.00007-1 · Cited by 123
“For example, phosphorylated STAT3 is then dimerized and translocated to the neuron nucleus, where it activates transcription of many genes (Heinrich et al., 2003).”
BackgroundProfile of sarilumab and its potential in the treatment of rheumatoid arthritis
Raimondo, M. G., Biggioggero, M., Crotti, C., Becciolini, A., & Favalli, E. G. (2017) · Drug Design Development and Therapy · doi:10.2147/dddt.s100302 · Cited by 121
“The complex IL-6/IL-6R is able to stimulate cells that constitutionally do not express the receptor by themselves through processes known as trans-signaling, whereas the transduction via the mIL-6R is called cis-signaling (Figure 1).(57) Studies evaluating the two different pathways were performed with designer protei…”
Theurich, S., Tsaousidou, E., Hanßen, R., Lempradl, A. M., Mauer, J., Timper, K., Schilbach, K., Folz‐Donahue, K., Heilinger, C., Sexl, V., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.05.018 · Cited by 127
Emerging roles for the IL-6 family of cytokines in pancreatic cancer
van Duijneveldt, G., Griffin, M. D. W., & Putoczki, T. L. (2020) · Clinical Science · doi:10.1042/cs20191211 · Cited by 126
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“Specifically, SOCS1 and 3, which are the most related with IL6 activation, inhibit the phosphorylation of gp130, resulting in a blockade of the JAK/STAT pathway (86).”
BackgroundIL6 Trans-signaling Promotes KRAS-Driven Lung Carcinogenesis
Brooks, G. D., McLeod, L., Alhayyani, S., Miller, A., Russell, P. A., Ferlin, W. G., Rose‐John, S., Ruwanpura, S. M., & Jenkins, B. J. (2016) · Cancer Research · doi:10.1158/0008-5472.can-15-2388 · Cited by 122
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Die Bedeutung der Zytokine in der posttraumatischen Entzündungsreaktion
Hildebrand, F., Pape, H., & Krettek, C. (2005) · Der Unfallchirurg · doi:10.1007/s00113-005-1005-1 · Cited by 119
Colitis-associated cancer: the role of T cells in tumor development
Waldner, M. J., & Neurath, M. F. (2009) · Seminars in Immunopathology · doi:10.1007/s00281-009-0161-8 · Cited by 124
“These receptors initiate a signal cascade involving Janusactivated kinase/signal transducers and activators of transcription (STAT) pathways and the mitogen-activated protein kinase pathway [26].”
Alveolar Epithelial STAT3, IL-6 Family Cytokines, and Host Defense during Escherichia coli Pneumonia
Quinton, L. J., Jones, M. R., Robson, B. E., Simms, B. T., Whitsett, J. A., & Mizgerd, J. P. (2008) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2007-0365oc · Cited by 118
“IL-6 is but one member of a family of cytokines bearing its name, all of which signal through STAT3 ( 14 ).”
BackgroundInfluentialLiao, Q., Zeng, Z., Guo, X., Li, X., Wei, F., Zhang, W., Li, X., Chen, P., Liang, F., Xiang, B., et al. (2013) · Oncogene · doi:10.1038/onc.2013.161 · Cited by 118
LIF signaling in stem cells and development
Onishi, K., & Zandstra, P. W. (2015) · Development · doi:10.1242/dev.117598 · Cited by 127
Neural Stem Cells, Neural Progenitors, and Neurotrophic Factors
Hsu, Y., Lee, D.-C., & Chiu, I. (2007) · Cell Transplantation · doi:10.3727/000000007783464678 · Cited by 115
Cytokines in alcoholic liver disease
An, L., Wang, X., & Cederbaum, A. I. (2012) · Archives of Toxicology · doi:10.1007/s00204-012-0814-6 · Cited by 116
Owaki, T., Asakawa, M., Fukai, F., Mizuguchi, J., & Yoshimoto, T. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.11.7579 · Cited by 121
“the regulation of various cytokine signalings (14, 15).”
BackgroundInterleukin-6 Induces Both Cell Growth and VEGF Production in Malignant Mesotheliomas
Adachi, Y., Aoki, C., Yoshio‐Hoshino, N., Takayama, K., Curiel, D. T., & Nishimoto, N. (2006) · International Journal of Cancer · doi:10.1002/ijc.22006 · Cited by 115
“As a result of gp130 engagement via IL-6 stimulation, the signal transducer and activator of transcription 3 (STAT3) also dimerizes and then translocates into the nucleus to induce the expression of target genes.(18)”
BackgroundKim, M., Nam, H.-J., Kim, H., Han, S., Im, S., Kim, T., Oh, D., & Bang, Y. (2013) · Cancer Letters · doi:10.1016/j.canlet.2013.02.010 · Cited by 117
“IL-6 is a major cytokine involved in STAT3 activation [28].”
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Roles of IL-6 in Ocular Inflammation: A Review
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“lating factor (G-CSF), GM-CSF, macrophage inflammatory protein (MIP)-1 and 2, and transforming growth factor (TGF)-β.(5) Detailed reviews on IL-8 and IL-10 effects in ocular inflammation have previously been published, 7 but there were not any detailed ocular-related IL-6 review in the medical literature.”
BackgroundImpact of Interleukin-6 in Hematological Malignancies
Burger, R. (2013) · Transfusion Medicine and Hemotherapy · doi:10.1159/000354194 · Cited by 118
“Mice deficient in Raf/mitogen-activated protein kinase (MAPK) cascade, and the phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) pathway [6].”
BackgroundQuaiser, T., & Mönnigmann, M. (2009) · BMC Systems Biology · doi:10.1186/1752-0509-3-50 · Cited by 114
“This is justified, because the key function of SOCS1 is not its binding to STAT, but its inhibition of the activated receptor complex [39].”
BackgroundInterleukin-6 inhibitors in the treatment of rheumatoid arthritis
Kavanaugh, A. (2008) · Therapeutics and Clinical Risk Management · doi:10.2147/tcrm.s3470 · Cited by 115
“The binding of IL-6R complexed with IL-6 results in homodi-merization of gp130 and signal transduction through Janus-activated kinase (JAK)/signal transducers and activators of transcription (STAT) pathways (Heinrich et al 2003).”
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“Long and short forms of vertebrate class 1 cytokine receptors can form heterodimers/multimers [17,41].”
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“Subsequently the signal-transduction pathways are actived, including the signal pathway of JAK-STATs (JAK-signal transducer and transcription activators), the signal pathway of Ras-MAPKs (Ras-mitogen activated protein kinase) and the signal pathway of PI3K-Akt (phosphoninositol-3 kinase-AKT) (9,10).”
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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