LPS hypersensitivity of gp130 mutant mice is independent of elevated haemopoietic TLR4 signaling

Claire J Greenhill, Jodee Ann Gould, Matthias R Ernst, Andrew G Jarnicki, Paul John Hertzog, Ashley Scott Mansell, Brendan John Jenkins

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)

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 kappa-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.Immunology and Cell Biology advance online publication,
Original languageEnglish
Pages (from-to)559 - 563
Number of pages5
JournalImmunology and Cell Biology
Volume90
Issue number5
DOIs
Publication statusPublished - 2012

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