Paraoxonase-1 Suppresses Experimental Colitis via the Inhibition of IFN-γ Production from CD4 T Cells
Paraoxonase-1 Suppresses Experimental Colitis via the Inhibition of IFN-γ Production from CD4 T Cells
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DOI：
10.4049/jimmunol.1201828
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发表时间：
2013-07-15
影响因子：
4.4
通讯作者：
Nakayama, Toshinori
中科院分区：
文献类型：
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作者：
Yamashita, Junji;Iwamura, Chiaki;Nakayama, Toshinori
克罗恩病（CD）是胃肠道的慢性炎症性疾病，其中观察到过度的Th 1细胞应答。我们进行了实验，以确定在人类血浆中的免疫生物活性蛋白质，并发现对氧磷酶（PON）-1，它具有酯酶活性，并与高密度脂蛋白，抑制IFN-γ的生产由小鼠和人类分化的Th 1细胞。三硝基苯磺酸诱导的结肠炎通过施用PON-1而减弱。PON-1的有益作用与肠系膜淋巴结中产生IFN-γ的CD 4 T细胞的比例降低和结肠中T细胞相关细胞因子的产生减少有关。PON-1可抑制TCR诱导的CD 4 T细胞ERK-MAPK信号通路的激活和NF-κ B B核转位。有趣的是，在生理和病理条件下，在PON-1缺陷小鼠中观察到过度的CD 4 T细胞应答。此外，PON-1或G3 C9-C284 A（G3 C9）（其显示出比PON-1更高的酯酶活性）对结肠炎的功效与抗TNF-α mAb（其是临床上使用的CD治疗）的功效相似。此外，G3 C9比PON-1更有效地抑制小鼠中CD 4（+）CD 45 RB（高）细胞转移诱导的慢性结肠炎，并且G3 C9对结肠炎的功效与抗TNF-α mAb的功效相似。因此，PON-1（或G3 C9）给药可能对CD患者有临床益处。
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-gamma 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-gamma-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-kappa B 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-alpha 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-alpha mAb. Therefore, PON-1 (or G3C9) administration may be clinically beneficial for CD patients.