- Title
- LPS hypersensitivity of gp130 mutant mice is independent of elevated haemopoietic TLR4 signaling
- Creator
- Greenhill, Claire J.; Gould, Jodee; Ernst, Matthias; Jarnicki, Andrew; Hertzog, Paul J.; Mansell, Ashley; Jenkins, Brendan J.
- Relation
- Immunology and Cell Biology Vol. 90, Issue 5, p. 559-563
- Publisher Link
- http://dx.doi.org/10.1038/icb.2011.56
- Publisher
- Nature Publishing Group
- Resource Type
- journal article
- Date
- 2012
- Description
- 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 gp130F/F mice. This regulation by IL-6 in gp130F/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 gp130F/F mice, are unknown. We report here that in LPS-treated macrophages from gp130F/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 gp130F/F immune cells is dispensable for the hypersensitivity of gp130F/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 gp130F/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 gp130F/F mice emphasizes non-haemopoietic gp130 signaling as a key regulator of systemic inflammatory responses during LPS-induced endotoxemia.
- Subject
- cytokine signaling; endotoxemia; gene microarray; interleukin-6; macrophages; Toll-like receptor 4
- Identifier
- http://hdl.handle.net/1959.13/1319103
- Identifier
- uon:23783
- Identifier
- ISSN:0818-9641
- Language
- eng
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