Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea.
Front Immunol. 2021 Feb 2;12:615803. doi: 10.3389/fimmu.2021.615803. eCollection 2021.
Uncontrolled macrophage functions cause failure to resolve gut inflammation and has been implicated in the pathogenesis of inflammatory bowel disease (IBD). 15-Deoxy-Δ-prostaglandin J (15d-PGJ), one of endogenous lipid mediators formed from arachidonic acid during the inflammatory process, has been reported to terminate inflammation. However, the pro-resolving effect of 15d-PGJ on intestinal inflammation and underlying molecular mechanisms remain largely unknown. In the present study, we examined the effects of 15d-PGJ on the resolution of dextran sulfate sodium (DSS)-induced murine colitis that mimics human IBD. Pharmacologic inhibition of prostaglandin D synthase (PGDS) responsible for the synthesis of 15d-PGJ hampered resolution of inflammation in the colonic mucosa of mice treated with DSS. Notably, intraperitoneal injection of 15d-PGJ accelerated the resolution of experimentally induced colitis. 15d-PGJ treatment reduced the number of neutrophils and M1 macrophages, while it increased the proportion of M2 macrophages. Moreover, 15d-PGJ treated mice exhibited the significantly reduced proportion of macrophages expressing the pro-inflammatory cytokine, IL-6 with concomitant suppression of STAT3 phosphorylation in the colonic mucosa of mice administered 2.5% DSS in drinking water. Taken together, these findings clearly indicate that 15d-PGJ, endogenously generated from arachidonic acid by cyclooxygenase-2 and PGDS activities in inflamed tissue, promotes resolution of intestinal colitis.
未受控制的巨噬细胞功能导致肠道炎症无法解决，并与炎症性肠病（IBD）的发病机制有关。15-脱氧-Δ-前列腺素 J（15d-PGJ）是在炎症过程中由花生四烯酸形成的内源性脂质介质之一，已被报道可终止炎症。然而，15d-PGJ 对肠道炎症的促解决作用及其潜在的分子机制在很大程度上仍不清楚。在本研究中，我们研究了 15d-PGJ 对模拟人类 IBD 的葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎消退的影响。负责合成 15d-PGJ 的前列腺素 D 合酶（PGDS）的药理抑制阻碍了 DSS 处理小鼠结肠黏膜中炎症的消退。值得注意的是，腹腔注射 15d-PGJ 可加速实验性诱导的结肠炎的消退。15d-PGJ 治疗减少了中性粒细胞和 M1 巨噬细胞的数量，同时增加了 M2 巨噬细胞的比例。此外，15d-PGJ 治疗的小鼠表现出显著减少表达促炎细胞因子 IL-6 的巨噬细胞的比例，同时伴随着在饮用水中给予 2.5%DSS 的小鼠结肠黏膜中 STAT3 磷酸化的抑制。综上所述，这些发现清楚地表明，15d-PGJ 由环氧化酶-2 和 PGDS 活性在炎症组织中从花生四烯酸内源性生成，可促进肠道结肠炎的消退。
