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LPS hypersensitivity of gp130 mutant mice is independent of elevated haemopoietic TLR4 signaling
Author(s) -
Greenhill Claire J,
Gould Jodee,
Ernst Matthias,
Jarnicki Andrew,
Hertzog Paul J,
Mansell Ashley,
Jenkins Brendan J
Publication year - 2011
Publication title -
immunology and cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0818-9641
DOI - 10.1038/icb.2011.56
Subject(s) - tlr4 , biology , signal transduction , glycoprotein 130 , microbiology and biotechnology , stat protein , immunology , stat3
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.