The pro- and anti-inflammatory properties of the cytokine interleukin-6
Open accessAbstract
Interleukin-6 is a cytokine not only involved in inflammation and infection responses but also in the regulation of metabolic, regenerative, and neural processes. In classic signaling, interleukin-6 stimulates target cells via a membrane bound interleukin-6 receptor, which upon ligand binding associates with the signaling receptor protein gp130. Gp130 dimerizes, leading to the activation of Janus kinases and subsequent phosphorylation of tyrosine residues within the cytoplasmic portion of gp130. This leads to the engagement of phosphatase Src homology domains containing tyrosin phosphatase-2 (SHP-2) and activation of the ras/raf/Mitogen-activated protein (MAP) kinase (MAPK) pathway. In addition, signal transducer and activator of transcription factors are recruited, which are phosphorylated, and consequently dimerize whereupon they translocate into the nucleus and activate target genes. Interestingly, only few cells express membrane bound interleukin-6 receptor whereas all cells display gp130 on the cell surface. While cells, which only express gp130, are not responsive to interleukin-6 alone, they can respond to a complex of interleukin-6 bound to a naturally occurring soluble form of the interleukin-6 receptor. Therefore, the generation of soluble form of the interleukin-6 receptor dramatically enlarges the spectrum of interleukin-6 target cells. This process has been named trans-signaling. Here, we review the involvement of both signaling modes in the biology of interleukin-6. It turns out that regenerative or anti-inflammatory activities of interleukin-6 are mediated by classic signaling whereas pro-inflammatory responses of interleukin-6 are rather mediated by trans-signaling. This is important since therapeutic blockade of interleukin-6 by the neutralizing anti-interleukin-6 receptor monoclonal antibody tocilizumab has recently been approved for the treatment of inflammatory diseases. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.
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IL-6 trans signaling leads to recruitment of monocytes to the inflammation site, promotes the maintenance of Th17 cells, and inhibits T cell apoptosis and development of Tregs.
“IL-6 trans signaling also leads to recruitment of monocytes to the inflammation site (42), promotes the maintenance of Th17 cells, and inhibits T cell apoptosis and development of Tregs (43).”
From Macrophage Cytokines: Involvement in Immunity and Infectious Diseases (2014) · cites this paper as [43]
IL-6 classic signaling mediates apoptosis inhibition and the regeneration of intestinal epithelial cells.
“IL-6 classic signaling also mediates apoptosis inhibition and the regeneration of intestinal epithelial cells (43).”
From Macrophage Cytokines: Involvement in Immunity and Infectious Diseases (2014) · cites this paper as [43]
C-reactive protein and IL-6 have been linked to immunosenescence in prior studies, but their relationship with systemic chronic inflammation had not been established.
“Canonical acute inflammation proteins such as C-reactive protein and interleukin (IL)-6 have been associated with immunosenescence in previous studies37,38, but the relationship with systemic chronic inflammation (SCI) has not yet been established.”
From An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging (2021) · cites this paper as [38]
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- Authors
- Scheller, J., Chalaris, A., Schmidt-Arras, D., & Rose-John, S.
- Affiliations
- Heinrich Heine University Düsseldorf (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- ORCID
- Scheller, Jürgen
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 1813
- Issue
- 5
- Pages
- 878-888
- ISSN
- 0167-4889 (ISSN-L)
- OpenAlex
- W2110463517
- Cited by
- 3,212
- References
- 14
- Citations by year
- 2026: 134 · 2025: 210 · 2024: 209 · 2023: 198 · 2022: 281 · 2021: 293 · 2020: 301 · 2019: 273 · 2018: 278 · 2017: 313 · 2016: 247 · 2015: 157 · 2014: 124 · 2013: 91 · 2012: 75
- FWCI
- 9.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft, Bonn, Germany (SFB415, SFB841, SFB877)
- Cluster of Excellence “Inflammation at Interfaces.”
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- interleukin-6, gp130, trans-signaling, soluble IL-6 receptor, Janus kinase signaling, SHP2, MAPK signaling, STAT3, inflammation, anti-inflammatory activity, regenerative effect, tocilizumab, cytokine signaling
- MeSH terms
- Animals, Anti-Inflammatory Agents, Humans, Models, Biological, Signal Transduction, Interleukin-6, Inflammation Mediators, Receptors, Interleukin-6
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