title: Extracellular ATP induces P2X7 receptor activation in mouse Kupffer cells, leading to release of IL-1β, HMGB1, and PGE2, decreased MHC class I expression and necrotic cell death.
abstract: Kupffer cells, which are resident macrophages in liver, can produce various cytokines and chemokines that induce hepatitis and liver fibrosis. It is suggested that extracellular ATP-induced activation of macrophage P2X7 receptor plays an important role in inflammation via release of pro-inflammatory mediators, but the role of P2X7 receptor in Kupffer cells remains unclear. Here, we show that activation of P2X7 receptor in Kupffer cells causes multiple inflammatory responses, using the clonal mouse Kupffer cell line (KUP5) that we previously established. Treatment of LPS-primed Kupffer cells with 3 mM ATP induced Ca(2+) influx, non-selective large pore formation, activation of MAPK, cell lysis, IL-1β release, prostaglandin E2 (PGE2) release, high mobility group box1 (HMGB1) release, and major histocompatibility complex (MHC) class I shedding. These events were significantly suppressed by pretreatment with P2X7 antagonist A438079, indicating involvement of P2X7 receptor activation in these inflammatory responses. Our results suggest that extracellular ATP-induced activation of P2X7 receptor of Kupffer cells plays multiple roles in the inflammatory response in liver. P2X7 receptor might be a new therapeutic target for treatment of liver diseases.
authors: Department of Radiation Biosciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba, Japan; Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan.
authors: Yusuke
authors: Y
authors: Toki
authors: Animal Immune and Cell Biology Research Unit, Division of Animal Sciences, National Institute of Agrobiological Sciences, 1-2 Ohwashi, Tsukuba, Ibaraki 305-8634, Japan.
authors: Takato
authors: T
authors: Takenouchi
authors: Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3 Minamitamagaki-cho, Suzuka-shi, Mie, Japan.
authors: Hitoshi
authors: H
authors: Harada
authors: Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan.
authors: Sei-ichi
authors: S
authors: Tanuma
authors: Animal Immune and Cell Biology Research Unit, Division of Animal Sciences, National Institute of Agrobiological Sciences, 1-2 Ohwashi, Tsukuba, Ibaraki 305-8634, Japan.
authors: Hiroshi
authors: H
authors: Kitani
authors: Department of Radiation Biosciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba, Japan.
authors: Shuji
authors: S
authors: Kojima
authors: Department of Radiation Biosciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba, Japan. Electronic address: tsukim@rs.noda.tus.ac.jp.
authors: Mitsutoshi
authors: M
authors: Tsukimoto
mesh_terms: D000255:Adenosine Triphosphate / Q000276:immunology*; D000818:Animals; D002478:Cells, Cultured; D015232:Dinoprostone / Q000276:immunology*; D024243:HMGB1 Protein / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology*; D007728:Kupffer Cells / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D058486:Receptors, Purinergic P2X7 / Q000276:immunology*
chemical_list: D024243:HMGB1 Protein; D015395:Histocompatibility Antigens Class I; D053583:Interleukin-1beta; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D015232:Dinoprostone
keywords: Cell death; Cytokine production; Inflammation; Kupffer cells; P2X7 receptor