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

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.