title: IL-6 trans-signaling modulates TLR4-dependent inflammatory responses via STAT3.
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.
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
authors.forename: Claire J
authors.initials: CJ
authors.lastname: Greenhill
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Rami
authors.initials: R
authors.lastname: Lissilaa
authors.forename: Walter
authors.initials: W
authors.lastname: Ferlin
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hertzog
authors.forename: Ashley
authors.initials: A
authors.lastname: Mansell
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Jenkins
mesh_terms: D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D050822:Cytokine Receptor gp130 / Q000235:genetics; D055879:Gene Knock-In Techniques; D018836:Inflammation Mediators / Q000502:physiology*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology*; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
chemical_list: C494200:Il6st protein, mouse; D018836:Inflammation Mediators; D015850:Interleukin-6; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C499045:TIRAP protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D050822:Cytokine Receptor gp130