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15-Deoxy-?^12,14-Prostaglandin J₂ Promotes Resolution of Experimentally Induced Colitis.

ABSTRACT: Uncontrolled macrophage functions cause failure to resolve gut inflammation and has been implicated in the pathogenesis of inflammatory bowel disease (IBD). 15-Deoxy-?^12,14-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.

SUBMITTER: Kim W

PROVIDER: S-EPMC7901909 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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15-Deoxy-△12,14-Prostaglandin J2 Promotes Resolution of Experimentally Induced Colitis.

Kim Wonki W Jang Jeong-Hoon JH Zhong Xiancai X Seo Hyungseok H Surh Young-Joon YJ

Frontiers in immunology 20210202

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 rema ...[more]

PMID: 33633749

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Project description:Background15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), one of the major metabolites from prostaglandin D2 in arachidonic acid metabolic pathway, has potential anti-inflammatory properties. The objective of this study was to explore the effects of 15d-PGJ2-loaded poly(D,L-lactide-co-glycolide) nanocapsules (15d-PGJ2-NC) on inflammatory responses and bone regeneration in local bone defect.MethodsThe study was conducted on 96 Wistar rats from June 2014 to March 2016. Saline, unloaded nanoparticles, free 15d-PGJ2or 15d-PGJ2-NC, were delivered through a collagen vehicle inside surgically created transcortical defects in rat femurs. Interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) levels in the surrounding soft tissue were analyzed by Western blot and in the defect by quantitative real-time polymerase chain reaction over 14 days. Simultaneously, bone morphogenetic protein-6 (BMP-6) and platelet-derived growth factor-B (PDGF-B) messenger RNA (mRNA) in the defect were examined. New bone formation and EphrinB2 and osteoprotegerin (OPG) protein expression in the cortical defect were observed by Masson's Trichrome staining and immunohistochemistry over 28 days. Data were analyzed by one-way analysis of variance. Least-significant difference and Dunnett's T3 methods were used with a bilateral P< 0.05.ResultsApplication of l5d-PGJ2-NC (100 μg/ml) in the local bone defect significantly decreased IL-6, IL-1β, and TNF-α mRNA and protein, compared with saline-treated controls (P < 0.05). l5d-PGJ2-NC upregulated BMP-6 and PDGF-B mRNA (P < 0.05). New bone formation was observed in the cortical defect in l5d-PGJ2-NC-treated animals from 7th day onward (P < 0.001). Expression of EphrinB2 and OPG presented early on day 3 and persisted through day 28 in 15d-PGJ2-NC group (P < 0.05).ConclusionStable l5d-PGJ2-NC complexes were prepared that could attenuate IL-6, IL-1β, and TNF-α expression, while increasing new bone formation and growth factors related to bone regeneration.

Project description:15-deoxy-?(12,14)-prostaglandin J2 (15d-PGJ2) is an anti-inflammatory downstream product of the cyclooxygenase enzymes. It has been implicated to play a protective role in a variety of inflammatory mediated diseases, including rheumatoid arthritis, neural damage, and myocardial infarctions. Here we show that 15d-PGJ2 also plays a role in Salmonella infection. Salmonella enterica Typhimurium is a Gram-negative facultative intracellular pathogen that is able to survive and replicate inside phagocytic immune cells, allowing for bacterial dissemination to systemic sites. Salmonella species cause a wide range of morbidity and mortality due to gastroenteritis and typhoid fever. Previously we have shown that in mouse models of typhoid fever, Salmonella infection causes a major perturbation in the prostaglandin pathway. Specifically, we saw that 15d-PGJ2 production was significantly increased in both liver and feces. In this work we show that 15d-PGJ2 production is also significantly increased in macrophages infected with Salmonella. Furthermore, we show that the addition of 15d-PGJ2 to Salmonella infected RAW264.7, J774, and bone marrow derived macrophages is sufficient to significantly reduce bacterial colonization. We also show evidence that 15d-PGJ2 is reducing bacterial uptake by macrophages. 15d-PGJ2 reduces the inflammatory response of these infected macrophages, as evidenced by a reduction in the production of cytokines and reactive nitrogen species. The inflammatory response of the macrophage is important for full Salmonella virulence, as it can give the bacteria cues for virulence. The reduction in bacterial colonization is independent of the expression of Salmonella virulence genes SPI1 and SPI2, and is independent of the 15d-PGJ2 ligand PPAR-?. 15d-PGJ2 also causes an increase in ERK1/2 phosphorylation in infected macrophages. In conclusion, we show here that 15d-PGJ2 mediates the outcome of bacterial infection, a previously unidentified role for this prostaglandin.

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15-Deoxy-?^12,14-Prostaglandin J₂ Promotes Resolution of Experimentally Induced Colitis.

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15-Deoxy-△<sup>12,14</sup>-Prostaglandin J<sub>2</sub> Promotes Resolution of Experimentally Induced Colitis.

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15-Deoxy-?12,14-Prostaglandin J2 Promotes Resolution of Experimentally Induced Colitis.

Publications

15-Deoxy-△<sup>12,14</sup>-Prostaglandin J<sub>2</sub> Promotes Resolution of Experimentally Induced Colitis.

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OmicsDI is part of the ELIXIR infrastructure

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15-Deoxy-?^12,14-Prostaglandin J₂ Promotes Resolution of Experimentally Induced Colitis.