IL-6 signal transduction and its physiological roles: the signal orchestration model
Abstract
Interleukin (IL)-6 is a pleiotropic cytokine that not only affects the immune system, but also acts in other biological systems and many physiological events in various organs. In a target cell, IL-6 can simultaneously generate functionally distinct or sometimes contradictory signals through its receptor complex, IL-6Ralpha and gp130. One good illustration is derived from the in vitro observations that IL-6 promotes the growth arrest and differentiation of M1 cells through gp130-mediated STAT3 activation, whereas the Y759/SHP-2-mediated cascade by gp130 stimulation has growth-enhancing effects. The final physiological output can be thought of as a consequence of the orchestration of the diverse signaling pathways generated by a given ligand. This concept, the signal orchestration model, may explain how IL-6 can elicit proinflammatory or anti-inflammatory effects, depending on the in vivo environmental circumstances. Elucidation of the molecular mechanisms underlying this issue is a challenging subject for future research. Intriguingly, recent in vivo studies indicated that the SHP-2-binding site- and YXXQ-mediated pathways through gp130 are not mutually exclusive but affect each other: a mutation at the SHP-2-binding site prolongs STAT3 activation, and a loss of STAT activation by gp130 truncation leads to sustained SHP-2/ERK MAPK phosphorylation. Although IL-6/gp130 signaling is a promising target for drug discovery for many human diseases, the interdependence of each signal…
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IL-10R has two motifs for STAT3 activation while the gp130 subunit of IL-6R has four, leading to IL-6R inducing a higher amplitude STAT3 signal.
“Another key difference between the IL-10R and the IL-6R, besides their differing interactions with SOCS3, is that the IL-10R has two motifs for STAT3 activation while the gp130 subunit of the IL-6R has four, leading to the IL-6R inducing a higher amplitude STAT3 signal [13], [27], [28].”
From A Model for How Signal Duration Can Determine Distinct Outcomes of Gene Transcription Programs (2012) · cites this paper as [28]
IL-6 is a pleiotropic cytokine involved in immune responses, inflammation, hematopoiesis, bone metabolism, embryonic development and other fundamental processes.
“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 [31]
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“Another key difference between the IL-10R and the IL-6R, besides their differing interactions with SOCS3, is that the IL-10R has two motifs for STAT3 activation while the gp130 subunit of the IL-6R has four, leading to the IL-6R inducing a higher amplitude STAT3 signal [13,27,28].”
- Authors
- Kamimura, D., Ishihara, K., & Hirano, T.
- Affiliations
- The University of Osaka (JP)
- RIKEN (JP)
- Corresponding author
- Hirano, T.
- Venue
- Reviews of Physiology, Biochemistry and Pharmacology
- Publisher
- Springer Berlin Heidelberg
- Published
- 2003-12-23
- Volume
- 149
- Pages
- 1-38
- OpenAlex
- W1809966404
- Cited by
- 673
- References
- 16
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 21 · 2023: 22 · 2022: 17 · 2021: 19 · 2020: 20 · 2019: 23 · 2018: 23 · 2017: 36 · 2016: 29 · 2015: 31 · 2014: 28 · 2013: 36 · 2012: 47
- FWCI
- 44.54
- Type
- book chapter
- Language
- en
- Open access
- closed
- Locations
- Springer eBooks (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- interleukin-6, STAT3 activation, SHP2, ERK signaling, IL-6 knockout mice, inflammatory diseases
- MeSH terms
- Acute-Phase Reaction, Amino Acid Sequence, Animals, Autoimmune Diseases, Bone and Bones, Hematopoiesis, Humans, Membrane Glycoproteins, Molecular Sequence Data, Mutation, Neoplasms, Neurosecretory Systems, Phenotype, Signal Transduction, Antigens, CD, Interleukin-6, Models, Immunological, Receptors, Interleukin-6, MAP Kinase Signaling System, Cytokine Receptor gp130
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