Paraoxonase-1 suppresses experimental colitis via the inhibition of IFN-γ production from CD4 T cells

• Published in: The Journal of immunology (1950) 2013-07, Vol.191 (2), p.949-960
• Main Authors: Yamashita, Junji, Iwamura, Chiaki, Ito, Toshihiro, Narita, Masakuni, Hara, Yukio, Sasaki, Tetsuya, Masuda, Daisuke, Takahashi, Munehisa, Tsuchiya, Manami, Hada, Kaori, Ishikawa, Makoto, Matsuo, Takato, Ohno, Yoichi, Tanaka, Hitoshi, Maruyama, Hideya, Ogawa, Yasumasa, Nakayama, Toshinori
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus; Amino Acid Sequence; Animals; Antibodies, Monoclonal - immunology; Aryldialkylphosphatase - genetics; Aryldialkylphosphatase - metabolism; Aryldialkylphosphatase - pharmacology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell Differentiation; Cell Line; CHO Cells; Colitis - chemically induced; Colitis - drug therapy; Colitis - immunology; Colitis - metabolism; Colon - metabolism; Colon - pathology; Cricetinae; Crohn Disease - drug therapy; Crohn Disease - immunology; Crohn Disease - metabolism; Female; Humans; Interferon-gamma - antagonists & inhibitors; Interferon-gamma - metabolism; Male; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, SCID; NF-kappa B - metabolism; Th1 Cells - immunology; Th1 Cells - metabolism; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1201828

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.