IL-6 Trans-Signaling Modulates TLR4-Dependent Inflammatory Responses via STAT3
Open accessAbstract
Innate immune responses triggered by the prototypical inflammatory stimulus LPS are mediated by TLR4 and involve the coordinated production of a multitude of inflammatory mediators, especially IL-6, which signals via the shared IL-6 cytokine family receptor subunit gp130. However, the exact role of IL-6, which can elicit either proinflammatory or anti-inflammatory responses, in the pathogenesis of TLR4-driven inflammatory disorders, as well as the identity of signaling pathways activated by IL-6 in a proinflammatory state, remain unclear. To define the contribution of gp130 signaling events to TLR4-driven inflammatory responses, we combined genetic and therapeutic approaches based on a series of gp130(F/F) knock-in mutant mice displaying hyperactivated IL-6-dependent JAK/STAT signaling in an experimental model of LPS/TLR4-mediated septic shock. The gp130(F/F) mice were markedly hypersensitive to LPS, which was associated with the specific upregulated production of IL-6, but not TNF-α. In gp130(F/F) mice, either genetic ablation of IL-6, Ab-mediated inhibition of IL-6R signaling or therapeutic blockade of IL-6 trans-signaling completely protected mice from LPS hypersensitivity. Furthermore, genetic reduction of STAT3 activity in gp130(F/F):Stat3(+/-) mice alleviated LPS hypersensitivity and reduced LPS-induced IL-6 production. Additional genetic approaches demonstrated that the TLR4/Mal pathway contributed to LPS hypersensitivity and increased IL-6 production in gp130(F/F) mice. Collectively, these data demonstrate for the first time, to our knowledge, that IL-6 trans-signaling via STAT3 is a critical modulator of LPS-driven proinflammatory responses through cross-talk regulation of the TLR4/Mal signaling pathway, and potentially implicate cross-talk between JAK/STAT and TLR pathways as a broader mechanism that regulates the severity of the host inflammatory response.
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The absolute level of IL6 detected fell in the middle range of reported levels in inflammatory contexts and above reported ranges post-exercise and diet-induced obesity.
“The absolute level of IL6 we detected fell in the middle range of reported levels (50 pg/mL to 200 ng/mL) in inflammatory contexts and above reported ranges post-exercise and diet-induced obesity (30-100 pg/mL) (Chowdhury et al.; Gao et al., 2014; Greenhill et al., 2011; Masuda et al., 2013; Osuchowski et al., 2006; Remick et al., 2005; Vida et al.; Wang et al., 2017; Yan et al., 2015).”
From Origin and function of stress-induced IL-6 in murine models (2020) · cites this paper as Greenhill et al., 2011
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Self-citation
- Authors
- Greenhill, C. J., Rose-John, S., Lissilaa, R., Ferlin, W., Ernst, M., Hertzog, P. J., Mansell, A., & Jenkins, B. J.
- Affiliations
- Monash University (AU)
- Institute of Biochemistry, Christian-Albrechts-University of Kiel , Kiel ,
- Light Chain Bioscience (Switzerland) (CH)
- Ludwig Cancer Research (BE)
- Corresponding author
- Mansell, Ashley
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-01
- Volume
- 186
- Issue
- 2
- Pages
- 1199-1208
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1904816508
- Cited by
- 264
- References
- 53
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 26 · 2023: 16 · 2022: 17 · 2021: 21 · 2020: 28 · 2019: 13 · 2018: 16 · 2017: 26 · 2016: 16 · 2015: 18 · 2014: 13 · 2013: 12 · 2012: 14
- FWCI
- 6.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (SFB 877)
- Monash University
- Exzellenzclusters Entzündungsforschung
- Medical Research Council
- National Health and Medical Research Council
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- IL-6 trans-signaling, TLR4, STAT3, gp130, lipopolysaccharide, septic shock, JAK/STAT signaling, innate immunity, inflammation, IL-6 receptor, signaling crosstalk
- MeSH terms
- Animals, Cells, Cultured, Cricetulus, Cricetinae, Male, Membrane Glycoproteins, Mice, Transgenic, Shock, Septic, Signal Transduction, Interleukin-6, Up-Regulation, CHO Cells, Rats, Wistar, Receptors, Interleukin-1, Mice, Knockout, Inflammation Mediators, STAT3 Transcription Factor, Cytokine Receptor gp130, Toll-Like Receptor 4, Mice, Rats, Myeloid Differentiation Factor 88, Gene Knock-In Techniques
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