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IL-6 trans-signalling modulates TLR4-dependent inflammatory responses via STAT1 and STAT3

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posted on 2017-01-31, 05:29 authored by Claire, Greenhill
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 pro- or anti-inflammatory responses, in the pathogenesis of TLR4-driven inflammatory disorders, as well as the identity of signalling pathways activated by IL-6 in a pro-inflammatory state, remain unclear. To define the contribution of gp130 signalling 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 signalling 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 TNFa. In gp130F/F mice, either genetic ablation of IL-6, antibody-mediated inhibition of IL-6 receptor signalling, or therapeutic blockade of IL-6 trans-signalling completely protected mice from LPS hypersensitivity. Furthermore, genetic reduction of STAT1 in gp130F/F:Stat1-/- mice and STAT3 activity in gp130F/F:Stat3+/- mice ameliorated LPS hypersensitivity and lowered LPS-induced IL-6 production. Additional genetic approaches demonstrated that the TLR4/Mal (Myd88 dependent) pathway contributed to LPS hypersensitivity and increased IL-6 production in gp130F/F mice. Furthermore, macrophages were not the cell type responsible for the LPS hypersensitivity of gp130F/F mice. Collectively, these data demonstrate for the first time that IL-6 trans-signalling via STAT1 and STAT3 is a critical modulator of LPS-driven pro-inflammatory responses through cross-talk regulation of the TLR4/Mal signalling 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. Moreover, it was found that anti-inflammatory IL-10 signalling was intact in the gp130F/F mice.

History

Principal supervisor

Brendan Jenkins

Year of Award

2011

Department, School or Centre

Hudson Institute of Medical Research

Additional Institution or Organisation

Centre of Innate Immunity and Inflammatory Diseases

Campus location

Australia

Course

Doctor of Philosophy

Degree Type

DOCTORATE

Faculty

Faculty of Medicine Nursing and Health Sciences

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    Faculty of Medicine, Nursing and Health Sciences Theses

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