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15-Deoxy-△12,14-Prostaglandin J2 Promotes Resolution of Experimentally Induced Colitis
Wonki Kim1, Jeong-Hoon Jang1, Xiancai Zhong1
1Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.
Abstract:
Uncontrolled macrophage functions cause failure to resolve gut inflammation and has been implicated in the pathogenesis of inflammatory bowel disease (IBD). 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), 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-PGJ2 on intestinal inflammation and underlying molecular mechanisms remain largely unknown. In the present study, we examined the effects of 15d-PGJ2 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-PGJ2 hampered resolution of inflammation in the colonic mucosa of mice treated with DSS. Notably, intraperitoneal injection of 15d-PGJ2 accelerated the resolution of experimentally induced colitis. 15d-PGJ2 treatment reduced the number of neutrophils and M1 macrophages, while it increased the proportion of M2 macrophages. Moreover, 15d-PGJ2 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-PGJ2, endogenously generated from arachidonic acid by cyclooxygenase-2 and PGDS activities in inflamed tissue, promotes resolution of intestinal colitis.
Insights
15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) helps resolve gut inflammation. This study shows 15d-PGJ2 treatment accelerates healing in colitis models by modulating macrophage function.
Area of Science:
- Immunology
- Gastroenterology
- Molecular Biology
Background:
- Uncontrolled macrophage activity impairs gut inflammation resolution, contributing to inflammatory bowel disease (IBD).
- 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is an endogenous lipid mediator with reported anti-inflammatory properties.
- The precise role and molecular mechanisms of 15d-PGJ2 in resolving intestinal inflammation are not fully understood.
Purpose of the Study:
- To investigate the therapeutic potential of 15d-PGJ2 in dextran sulfate sodium (DSS)-induced murine colitis, a model mimicking human IBD.
- To elucidate the underlying molecular mechanisms by which 15d-PGJ2 influences the resolution of intestinal inflammation.
Main Methods:
- Utilized a DSS-induced murine colitis model to mimic human IBD.
- Administered 15d-PGJ2 intraperitoneally and assessed its effects on inflammatory markers.
- Pharmacologically inhibited prostaglandin D synthase (PGDS) to evaluate its role in 15d-PGJ2 synthesis and inflammation resolution.
- Analyzed immune cell populations (neutrophils, M1/M2 macrophages) and molecular signaling pathways (STAT3 phosphorylation, IL-6 expression) in colonic tissue.
Main Results:
- Inhibition of PGDS, the enzyme synthesizing 15d-PGJ2, worsened colitis resolution.
- Intraperitoneal administration of 15d-PGJ2 significantly accelerated the resolution of DSS-induced colitis.
- 15d-PGJ2 treatment decreased neutrophil and M1 macrophage counts while increasing M2 macrophage proportions.
- Reduced expression of the pro-inflammatory cytokine IL-6 and suppressed STAT3 phosphorylation were observed in 15d-PGJ2-treated mice.
Conclusions:
- Endogenous 15d-PGJ2, generated by cyclooxygenase-2 and PGDS in inflamed tissues, plays a crucial role in promoting intestinal colitis resolution.
- Exogenous 15d-PGJ2 administration demonstrates therapeutic efficacy in resolving experimental colitis by modulating macrophage polarization and suppressing pro-inflammatory signaling.
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