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IL-6 Trans-Signaling Modulates TLR4-Dependent Inflammatory Responses via STAT3

Claire J. Greenhill, Stefan Rose-John, Rami Lissilaa, Walter Ferlin, Matthias Ernst, Paul J. Hertzog, Ashley Mansell and Brendan J. Jenkins
J Immunol January 15, 2011, 186 (2) 1199-1208; DOI: https://doi.org/10.4049/jimmunol.1002971
Claire J. Greenhill
*Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia;
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Stefan Rose-John
†Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany;
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Rami Lissilaa
‡NovImmune SA, Geneva, Switzerland; and
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Walter Ferlin
‡NovImmune SA, Geneva, Switzerland; and
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Matthias Ernst
§Ludwig Institute for Cancer Research, Parkville, Victoria, Australia
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Paul J. Hertzog
*Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia;
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Ashley Mansell
*Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia;
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Brendan J. Jenkins
*Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia;
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Abstract

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 gp130F/F knock-in mutant mice displaying hyperactivated IL-6–dependent JAK/STAT signaling in an experimental model of LPS/TLR4-mediated septic shock. The gp130F/F mice were markedly hypersensitive to LPS, which was associated with the specific upregulated production of IL-6, but not TNF-α. In gp130F/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 gp130F/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 gp130F/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.

Footnotes

  • This work was supported by a National Health and Medical Research Council of Australia Project grant (to B.J.J.), a Monash University Research Scholarship (to C.J.G.), an R.D. Wright Biomedical Fellowship (to A.M.), a National Health and Medical Research Council Senior Principal Research Fellowship (to P.J.H.), a Sylvia and Charles Viertel Foundation Senior Medical Research Fellowship (to B.J.J.), and a Monash University Fellowship (to B.J.J.). The work of S.R.-J. was supported by the Deutsche Forschungsgemeinschaft (SFB 877, TP A 1) and by the Cluster of Excellence Inflammation at Interfaces.

  • Abbreviations used in this article:

    CHO
    Chinese hamster ovary
    CLP
    cecal ligation and puncture
    IBD
    inflammatory bowel disease
    qPCR
    quantitative real-time PCR
    RA
    rheumatoid arthritis
    sIL-6Rα
    soluble IL-6Rα
    SOCS3
    suppressor of cytokine signaling 3.

  • Received September 2, 2010.
  • Accepted November 8, 2010.
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The Journal of Immunology: 186 (2)
The Journal of Immunology
Vol. 186, Issue 2
15 Jan 2011
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IL-6 Trans-Signaling Modulates TLR4-Dependent Inflammatory Responses via STAT3
Claire J. Greenhill, Stefan Rose-John, Rami Lissilaa, Walter Ferlin, Matthias Ernst, Paul J. Hertzog, Ashley Mansell, Brendan J. Jenkins
The Journal of Immunology January 15, 2011, 186 (2) 1199-1208; DOI: 10.4049/jimmunol.1002971

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IL-6 Trans-Signaling Modulates TLR4-Dependent Inflammatory Responses via STAT3
Claire J. Greenhill, Stefan Rose-John, Rami Lissilaa, Walter Ferlin, Matthias Ernst, Paul J. Hertzog, Ashley Mansell, Brendan J. Jenkins
The Journal of Immunology January 15, 2011, 186 (2) 1199-1208; DOI: 10.4049/jimmunol.1002971
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