IL-27 affects helper T cell responses via regulation of PGE2 production by macrophages |
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Authors: | Yayoi Sato Hiromitsu Hara Toshiaki Okuno Naoko Ozaki Shinobu Suzuki Takehiko Yokomizo Tsuneyasu Kaisho Hiroki Yoshida |
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Institution: | 1. Dept. of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga 849-8501, Japan;2. Dept. of Molecular & Cellular Biology, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., Kobe 650-0047, Japan;3. Lab Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan;4. Dept. of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan |
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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. |
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Keywords: | DC dendritic cell PG prostaglandin COX cyclooxygenase BMDM bone marrow-derived macrophage BM bone marrow CM conditioned medium mPGES-1 microsomal prostaglandin E2 synthase-1 cPGES-1 cytosolic prostaglandin E2 synthase H-PGDS hematopoietic prostaglandin D synthase APCs antigen presenting cells |
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