title: NOX1/NADPH Oxidase Expressed in Colonic Macrophages Contributes to the Pathogenesis of Colonic Inflammation in Trinitrobenzene Sulfonic Acid-Induced Murine Colitis.
abstract: NOX1/NADPH oxidase, a nonphagocytic isoform of reactive oxygen species-producing enzymes, is highly expressed in the colon, but the physiologic and pathophysiologic roles of this isoform are not fully understood. The present study investigated the role of NOX1 in the development of colonic inflammation in a trinitrobenzene sulfonic acid (TNBS)-induced murine colitis model. Intrarectal injection of TNBS caused severe colitis accompanied by body weight loss, diarrhea, and increased myeloperoxidase (MPO) activity in wild-type (WT) mice. In contrast, the severity of colitis was significantly attenuated in NOX1-deficient (NOX1KO) mice (the inhibitions of macroscopic damage score, body weight loss, diarrhea score, and MPO activity were 73.1%, 36.8%, 83.3%, and 98.4%, respectively). TNBS-induced upregulation of inflammatory cytokines (tumor necrosis factor (TNF)-α and interleukin (IL)-1β), chemokines (CXCL1 and CXLC2), and inducible nitric oxide synthase (iNOS) was also significantly less in NOX1KO than in WT mice (the inhibitions were 100.8%, 89.0%, 63.5%, 96.7%, and 97.1%, respectively). Expression of NOX1 mRNA was detected not only in the lamina propria but also in peritoneal macrophages isolated from WT mice. Increased expression of TNF-α, IL-1β, and iNOS in peritoneal macrophages exposed to lipopolysaccharide was significantly attenuated in macrophages isolated from NOX1KO mice (68.1%, 67.0%, and 79.3% inhibition, respectively). These findings suggest that NOX1/NADPH oxidase plays an important role in the pathogenesis of TNBS-induced colonic inflammation via upregulation of inflammatory cytokines, chemokines, and iNOS. NOX1 in colonic macrophages may become a potential target in pharmacologic intervention for inflammatory bowel disease.
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University (H.Y., A.T., Y. S., A. I., D. U., T. T., K. A., S.K.), and Department of Pharmacology, Kyoto Prefectural University of Medicine (M.M., K.I., C.Y-N.), Kyoto, Japan, and Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Gunma, Japan (A.N.).
authors.forename: Haruka
authors.initials: H
authors.lastname: Yokota
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University (H.Y., A.T., Y. S., A. I., D. U., T. T., K. A., S.K.), and Department of Pharmacology, Kyoto Prefectural University of Medicine (M.M., K.I., C.Y-N.), Kyoto, Japan, and Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Gunma, Japan (A.N.).
authors.forename: Ayaka
authors.initials: A
authors.lastname: Tsuzuki
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University (H.Y., A.T., Y. S., A. I., D. U., T. T., K. A., S.K.), and Department of Pharmacology, Kyoto Prefectural University of Medicine (M.M., K.I., C.Y-N.), Kyoto, Japan, and Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Gunma, Japan (A.N.).
authors.forename: Yuki
authors.initials: Y
authors.lastname: Shimada
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University (H.Y., A.T., Y. S., A. I., D. U., T. T., K. A., S.K.), and Department of Pharmacology, Kyoto Prefectural University of Medicine (M.M., K.I., C.Y-N.), Kyoto, Japan, and Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Gunma, Japan (A.N.).
authors.forename: Azusa
authors.initials: A
authors.lastname: Imai
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University (H.Y., A.T., Y. S., A. I., D. U., T. T., K. A., S.K.), and Department of Pharmacology, Kyoto Prefectural University of Medicine (M.M., K.I., C.Y-N.), Kyoto, Japan, and Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Gunma, Japan (A.N.).
authors.forename: Daichi
authors.initials: D
authors.lastname: Utsumi
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University (H.Y., A.T., Y. S., A. I., D. U., T. T., K. A., S.K.), and Department of Pharmacology, Kyoto Prefectural University of Medicine (M.M., K.I., C.Y-N.), Kyoto, Japan, and Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Gunma, Japan (A.N.).
authors.forename: Takuya
authors.initials: T
authors.lastname: Tsukahara
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University (H.Y., A.T., Y. S., A. I., D. U., T. T., K. A., S.K.), and Department of Pharmacology, Kyoto Prefectural University of Medicine (M.M., K.I., C.Y-N.), Kyoto, Japan, and Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Gunma, Japan (A.N.).
authors.forename: Misaki
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University (H.Y., A.T., Y. S., A. I., D. U., T. T., K. A., S.K.), and Department of Pharmacology, Kyoto Prefectural University of Medicine (M.M., K.I., C.Y-N.), Kyoto, Japan, and Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Gunma, Japan (A.N.).
authors.forename: Kikuko
authors.initials: K
authors.lastname: Amagase
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University (H.Y., A.T., Y. S., A. I., D. U., T. T., K. A., S.K.), and Department of Pharmacology, Kyoto Prefectural University of Medicine (M.M., K.I., C.Y-N.), Kyoto, Japan, and Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Gunma, Japan (A.N.).
authors.forename: Kazumi
authors.initials: K
authors.lastname: Iwata
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University (H.Y., A.T., Y. S., A. I., D. U., T. T., K. A., S.K.), and Department of Pharmacology, Kyoto Prefectural University of Medicine (M.M., K.I., C.Y-N.), Kyoto, Japan, and Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Gunma, Japan (A.N.).
authors.forename: Akio
authors.initials: A
authors.lastname: Nakamura
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University (H.Y., A.T., Y. S., A. I., D. U., T. T., K. A., S.K.), and Department of Pharmacology, Kyoto Prefectural University of Medicine (M.M., K.I., C.Y-N.), Kyoto, Japan, and Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Gunma, Japan (A.N.).
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yabe-Nishimura
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University (H.Y., A.T., Y. S., A. I., D. U., T. T., K. A., S.K.), and Department of Pharmacology, Kyoto Prefectural University of Medicine (M.M., K.I., C.Y-N.), Kyoto, Japan, and Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Gunma, Japan (A.N.) skato@mb.kyoto-phu.ac.jp.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kato
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced* / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D003106:Colon / Q000276:immunology*; D003967:Diarrhea / Q000150:complications; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D055786:Gene Knockout Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics*; D000074624:NADPH Oxidase 1; D009195:Peroxidase / Q000378:metabolism; D000067996:RAW 264.7 Cells; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D008070:Lipopolysaccharides; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014302:Trinitrobenzenesulfonic Acid; D009195:Peroxidase; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse