title: IL-27 promotes nitric oxide production induced by LPS through STAT1, NF-κB and MAPKs.
abstract: Interleukin (IL)-27, a member of the IL-6/IL-12 heterodimeric cytokine family, induces pro-inflammatory responses including early T helper (Th)1 differentiation and generation of cytotoxic T lymphocytes, and also anti-inflammatory responses including the differentiation to IL-10-producing regulatory T cells, inhibition of Th2 and Th17 differentiation, and suppression of pro-inflammatory cytokine production. Nitric oxide (NO) is a potent source of reactive nitrogen species that play an important role in killing intracellular pathogens and forms a crucial component of host defense. Inducible NO synthase (iNOS), which catalyzes the production of NO, is induced by a range of stimuli including cytokines and microbes. Recently, IL-27 was reported to play an anti-inflammatory role in microglia by blocking oncostatin M-induced iNOS expression and neuronal toxicity. In the present study, we investigated the effects of IL-27 on NO production in thioglycollate-elicited peritoneal macrophages. IL-27 together with lipopolysaccharide (LPS) induced morphological change into more spread and elongated cells and synergistically enhanced NO production. The combined stimulation also enhanced iNOS mRNA expression and the NO production was abrogated by an iNOS inhibitor, NG-monomethyl L-arginine. The synergistic NO production could be attributed to the augmented Toll-like receptor (TLR)4 mRNA expression by the combination. Signal transducer and activator of transcription (STAT)1 was indispensable for the morphological change and NO production. The combination induced nuclear factor κB (NF-κB) translocation into nuclear and phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), and their inhibitors suppressed NO production. These results suggest that in contrast to the anti-proinflammatory role in microglia, IL-27 exerts a pro-inflammatory role by enhancing NO production in peritoneal macrophages stimulated with LPS through activation of STAT1, NF-κB and MAPKs.
authors.affiliation: Tumor Therapy Laboratory, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
authors.forename: Motomu
authors.initials: M
authors.lastname: Shimizu
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ogura
authors.forename: Izuru
authors.initials: I
authors.lastname: Mizoguchi
authors.forename: Yukino
authors.initials: Y
authors.lastname: Chiba
authors.forename: Kaname
authors.initials: K
authors.lastname: Higuchi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Ohtsuka
authors.forename: Junichiro
authors.initials: J
authors.lastname: Mizuguchi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshimoto
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000276:immunology; D000818:Animals; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000276:immunology; D007378:Interleukins / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000276:immunology* / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis / Q000276:immunology*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000276:immunology* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; C486767:Il27 protein, mouse; D007378:Interleukins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases