title: IL-27 affects helper T cell responses via regulation of PGE2 production by macrophages.
abstract: IL-27 is a heterodimeric cytokine that regulates both innate and adaptive immunity. The immunosuppressive effect of IL-27 largely depends on induction of IL-10-producing Tr1 cells. To date, however, effects of IL-27 on regulation of immune responses via mediators other than cytokines remain poorly understood. To address this issue, we examined immunoregulatory effects of conditional medium of bone marrow-derived macrophages (BMDMs) from WSX-1 (IL-27Rα)-deficient mice and found enhanced IFN-γ and IL-17A secretion by CD4(+) T cells as compared with that of control BMDMs. We then found that PGE2 production and COX-2 expression by BMDMs from WSX-1-deficient mice was increased compared to control macrophages in response to LPS. The enhanced production of IFN-γ and IL-17A was abolished by EP2 and EP4 antagonists, demonstrating PGE2 was responsible for enhanced cytokine production. Murine WSX-1-expressing Raw264.7 cells (mWSX-1-Raw264.7) showed phosphorylation of both STAT1 and STAT3 in response to IL-27 and produced less amounts of PGE2 and COX-2 compared to parental RAW264.7 cells. STAT1 knockdown in parental RAW264.7 cells and STAT1-deficiency in BMDMs showed higher COX-2 expression than their respective control cells. Collectively, our result indicated that IL-27/WSX-1 regulated PGE2 secretion via STAT1-COX-2 pathway in macrophages and affected helper T cell response in a PGE2-mediated fashion.
authors.affiliation: Dept. of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga 849-8501, Japan; Dept. of Molecular & Cellular Biology, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., Kobe 650-0047, Japan; Lab Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan.
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Dept. of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga 849-8501, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Hara
authors.affiliation: Dept. of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Okuno
authors.affiliation: Dept. of Molecular & Cellular Biology, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., Kobe 650-0047, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Ozaki
authors.affiliation: Dept. of Molecular & Cellular Biology, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., Kobe 650-0047, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Dept. of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Yokomizo
authors.affiliation: Lab Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan.
authors.forename: Tsuneyasu
authors.initials: T
authors.lastname: Kaisho
authors.affiliation: Dept. of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga 849-8501, Japan. Electronic address: yoshidah@med.saga-u.ac.jp.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D002460:Cell Line; D017077:Culture Media, Conditioned; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis*; D005260:Female; D055785:Gene Knockdown Techniques; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D007378:Interleukins / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018121:Receptors, Cytokine / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018123:Receptors, Interleukin; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; C098680:Il17a protein, mouse; C486767:Il27 protein, mouse; C484747:Il27ra protein, mouse; D020381:Interleukin-17; D007378:Interleukins; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D007371:Interferon-gamma; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone
keywords: COX-2; Helper T cells; IL-27; Macrophage; Prostaglandin