title: LPS hypersensitivity of gp130 mutant mice is independent of elevated haemopoietic TLR4 signaling.
abstract: Among the many inflammatory mediators induced by the prototypical inflammatory stimulus lipopolysaccharide (LPS), which signals via Toll-like receptor (TLR)-4, interleukin (IL)-6 has recently been shown to feedback and augment TLR4 signaling when overproduced in LPS hypersensitive gp130(F/F) mice. This regulation by IL-6 in gp130(F/F) mice requires hyperactivation of the latent transcription factor signal transducer and activator of transcription (STAT) 3 via the IL-6 signaling receptor subunit gp130. However, the identity of LPS/TLR4-responsive inflammatory signaling pathways and gene networks, which are modulated by IL-6 (via gp130/STAT3), and the extent to which the tissue and cellular context of this regulation contributes to LPS-induced endotoxic shock in gp130(F/F) mice, are unknown. We report here that in LPS-treated macrophages from gp130(F/F) mice, gp130 hyperactivation upregulated the LPS-induced expression of inflammatory mediators downstream of Janus kinase (JAK)/STAT, nuclear factor κ-light-chain-enhancer of activated B cells, interferon regulatory factor and c-Jun N-terminal kinase/p38 mitogen-activated protein kinase pathways. Notably, however, LPS administration to bone marrow chimeras indicated that heightened LPS/TLR4 signaling in haemopoietic-derived gp130(F/F) immune cells is dispensable for the hypersensitivity of gp130(F/F) mice to LPS-induced endotoxemia. To understand the molecular consequences of gp130 hyperactivity in non-haemopoietic tissue on LPS-induced systemic inflammation, global gene expression profiling of livers from LPS-treated gp130(F/F) mice was performed and identified 264 hepatic LPS-responsive genes, which are differentially regulated by hyperactive gp130 signaling. Collectively, the substantial transcriptional reprogramming of LPS-responsive genes in gp130(F/F) mice emphasizes non-haemopoietic gp130 signaling as a key regulator of systemic inflammatory responses during LPS-induced endotoxemia.
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: Jodee
authors.initials: J
authors.lastname: Gould
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
authors.forename: Andrew
authors.initials: A
authors.lastname: Jarnicki
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; D050822:Cytokine Receptor gp130 / Q000235:genetics; D020869:Gene Expression Profiling; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000235:genetics; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D009154:Mutation / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D018183:Transplantation Chimera
chemical_list: C494200:Il6st protein, mouse; D015850:Interleukin-6; D008070:Lipopolysaccharides; D050796:STAT3 Transcription Factor; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D050822:Cytokine Receptor gp130