IL-6 trans-signaling modulates TLR4-dependent inflammatory responses via STAT3

CJ Greenhill, S Rose-John, R Lissilaa… - The Journal of …, 2011 - journals.aai.org
CJ Greenhill, S Rose-John, R Lissilaa, W Ferlin, M Ernst, PJ Hertzog, A Mansell, BJ Jenkins
The Journal of Immunology, 2011journals.aai.org
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 …
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 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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