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Cited by 3,272Cytokine Signaling Pathways and InteractionsProtein Tyrosine PhosphatasesNF-κB Signaling Pathways

The DOI matches its Crossref record; 268 of the 268 references it cites were found in a registry or an index; none of the 253 sources its claims cite is checked for support yet.

Principles of interleukin (IL)-6-type cytokine signalling and its regulation

Open access
HEINRICH, Peter C., BEHRMANN, Iris, HAAN, Serge, HERMANNS, Heike M., MÜLLER-NEWEN, Gerhard, SCHAPER, Fred·2003·Biochemical Journal
DOI 10.1042/bj20030407PMC PMC1223585
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Abstract

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.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1042/bj20030407

Cites

268 of 268 references verified0 citation errors · 0 not checkable

Statistics

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Verification

Claims the paper makes

0 of 253 cited sources checked · 0 supported · 0 flagged

Show all 147 claims

  • Probably not a substantial claim. 16
  • It may state two separate claims as one. 55
67 of 67

  • 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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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
ORCID
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
DOI
10.1042/bj20030407
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
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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