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

摘要: Innate immune responses triggered by the prototypical inflammatory stimulus LPS are mediated TLR4 and involve coordinated production of a multitude mediators, especially IL-6, which signals via shared IL-6 cytokine family receptor subunit gp130. However, exact role can elicit either proinflammatory or anti-inflammatory responses, in pathogenesis TLR4-driven disorders, as well identity signaling pathways activated state, remain unclear. To define contribution gp130 events to we combined genetic therapeutic approaches based on series gp130(F/F) knock-in mutant mice displaying hyperactivated IL-6-dependent JAK/STAT an experimental model LPS/TLR4-mediated septic shock. The were markedly hypersensitive LPS, was associated with specific upregulated but not TNF-α. In mice, ablation Ab-mediated inhibition IL-6R blockade trans-signaling completely protected from hypersensitivity. Furthermore, reduction STAT3 activity gp130(F/F):Stat3(+/-) alleviated hypersensitivity reduced LPS-induced production. Additional demonstrated that TLR4/Mal pathway contributed increased mice. Collectively, these data demonstrate for first time, our knowledge, is critical modulator LPS-driven through cross-talk regulation pathway, potentially implicate between TLR broader mechanism regulates severity host response.