A pro-resolution mediator, prostaglandin D ₂ , is specifically up-regulated in individuals in long-term remission from ulcerative colitis

Abstract

Patients with ulcerative colitis (UC) experience unpredictable bouts of active inflammation and ulceration. Relatively little attention has been paid to the role of antiinflammatory mediators in the pathogenesis of UC, although rodent studies suggest an important role of prostaglandin (PG) D 2 in the resolution of tissue injury and inflammation. The present study was performed to determine if colonic PGD 2 synthesis was altered in patients in remission from UC and if expression of the key enzymes and receptors related to PGD 2 was altered. During routine colon-cancer screening, colonic biopsies were obtained from healthy individuals, some of whom had been in remission from UC, without treatment, for >4 y. UC patients with active disease or in medically induced remission were also biopsied. Only patients with active UC exhibited elevated expression of several proinflammatory cytokines (TNFα and IFNγ) and colonic PGE 2 synthesis. In contrast, colonic PGD 2 synthesis was only elevated (∼3-fold) in the healthy individuals with a prior history of UC. This group also exhibited significantly elevated expression of DP1, the key receptor mediating the antiinflammatory actions of PGD 2 . Expression of the synthetic enzymes cyclooxygenase-1, cyclooxygenase-2, and hematopoietic PGD synthase was not altered in the healthy individuals with a prior history of UC. These results show a marked up-regulation of synthesis of an antiinflammatory prostanoid and expression of its receptor, specifically in individuals in long-term remission from UC. This is consistent with animal studies showing the importance of PGD 2 in the induction and maintenance of remission from colitis.inflammation | inflammatory bowel disease | eicosanoid | colon cancer

Resolvin D1 Improves the Resolution of Inflammation via Activating NF-κB p50/p50–Mediated Cyclooxygenase-2 Expression in Acute Respiratory Distress Syndrome

“…Several studies have demonstrated that PGE 2 , the most abundant and prominent prostanoid in inflammation initiation, is involved in the processes leading to the classical signs of inflammation (36,37). In contrast, PGD 2 par- ticipates in the control of resolution with its prolonged elevation during the later phase of inflammation (13,38,39). Consistent with these reports, our study clearly showed that, in both ex vitro and in vivo experiments, COX-2 was activated throughout the inflammatory response period.…”

“…In addition to its well-known role as a pharmaceutical target for anti-inflammatory drugs in inflammatory diseases, COX-2 also exerts versatile biological activities to resolve inflammation (7)(8)(9). At the onset of inflammation, COX-2 has a potent proinflammatory effect, predominantly through the generation of PGE 2 , whereas in the resolution phase, COX-2 is responsible for producing proresolving PGs, such as PGD 2 , 15-deoxy-D 12,14 -PGJ 2 , and PGF 2a (10)(11)(12)(13). Notably, PGE 2 and PGD 2 are responsible for modulating lipid mediator class switching from proinflammation to proresolution, as they have been shown to initiate the production of 15-lipoxygenase, a pivotal enzyme that is capable of mediating the biosynthesis of proresolving lipid mediators (14).…”

Cryptogenic multifocal ulcerating stenosing enteritis associated with homozygous deletion mutations in cytosolic phospholipase A2-α

“…Furthermore, these individuals would be expected to be deficient in a number of COX-2 products, such as prostaglandin D 2 39 and 15-deoxy-Δ12 14-prostaglandin J 2 40—as well as the lipoxygenase-produced lipoxins41—which have key anti-inflammatory and pro-resolution roles. Prostaglandin D 2 , for example, has been shown to be specifically upregulated in the long-term remission of ulcerative colitis,42 illustrating a gastrointestinal-protective effect, which would presumably be lacking in these individuals. In this way, mucosal injury can initiate a vicious cycle of ulceration and fibrosis as the lesions persist in the presence of impaired resolution.…”

Prostaglandine D2 et homéostasie de la barrière épithéliale intestinale

“…En effet, une surexpression de DP1 associée à une augmentation de la production de PGD2 est observée chez les patients en rémission par rapport aux patients en phase active de la maladie [6]. À l'inverse, un effet délétère de la PGD2 a été évoqué dans un modèle de colite induite par instillation d'acide trinitrobenzène sulphonique [22].…”

“…Néanmoins, son rôle dans le contrôle de l'homéostasie de la barrière épithéliale intestinale n'est que partiellement élucidé. Les données de la littérature suggèrent qu'au cours des maladies inflammatoires chroniques de l'intestin, la production de PGD2 est plus tardive que celle de PGE2, mais qu'elle serait persistante et contemporaine de la résolution de certains processus inflammatoires [5][6][7]. Deux études récentes portant sur des patients atteints de rectocolite hémorragique montrent l'implication de ce médiateur lipidique dans la physiopathologie de ces maladies inflammatoires [6,8].…”