title: Paraoxonase-1 suppresses experimental colitis via the inhibition of IFN-γ production from CD4 T cells.
abstract: Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract, where excessive Th1 cell responses are observed. We performed experiments to identify immunologically bioactive proteins in human plasma and found that paraoxonase (PON)-1, which has esterase activity and is associated with high-density lipoproteins, inhibited the IFN-γ production by both murine and human differentiating Th1 cells. Trinitrobenzene sulfonic acid-induced colitis was attenuated by the administration of PON-1. The beneficial effects of PON-1 were associated with a reduced ratio of IFN-γ-producing CD4 T cells in the mesenteric lymph nodes and decreased production of T cell-related cytokines in the colon. PON-1 inhibited the TCR-induced activation of ERK-MAPK signaling and the nuclear translocation of NF-κB in CD4 T cells. Interestingly, an excessive CD4 T cell response was observed in PON-1-deficient mice under physiological and pathological conditions. Additionally, the efficacy of PON-1 or G3C9-C284A (G3C9), which shows a higher esterase activity than PON-1, on colitis was similar to that of an anti-TNF-α mAb, which is a clinically used CD treatment. Moreover, G3C9 more effectively suppressed CD4(+)CD45RB(high) cell transfer-induced chronic colitis in mice than did PON-1, and the efficacy of G3C9 against the colitis was similar to that of the anti-TNF-α mAb. Therefore, PON-1 (or G3C9) administration may be clinically beneficial for CD patients.
authors.affiliation: Department of Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Yamashita
authors.forename: Chiaki
authors.initials: C
authors.lastname: Iwamura
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Ito
authors.forename: Masakuni
authors.initials: M
authors.lastname: Narita
authors.forename: Yukio
authors.initials: Y
authors.lastname: Hara
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Sasaki
authors.forename: Daisuke
authors.initials: D
authors.lastname: Masuda
authors.forename: Munehisa
authors.initials: M
authors.lastname: Takahashi
authors.forename: Manami
authors.initials: M
authors.lastname: Tsuchiya
authors.forename: Kaori
authors.initials: K
authors.lastname: Hada
authors.forename: Makoto
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Takato
authors.initials: T
authors.lastname: Matsuo
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ohno
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Tanaka
authors.forename: Hideya
authors.initials: H
authors.lastname: Maruyama
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Ogawa
authors.forename: Toshinori
authors.initials: T
authors.lastname: Nakayama
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D043303:Aryldialkylphosphatase / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016466:CHO Cells; D002454:Cell Differentiation; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D003106:Colon / Q000378:metabolism / Q000473:pathology; D006224:Cricetinae; D003424:Crohn Disease / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D014302:Trinitrobenzenesulfonic Acid; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human