Opposing Roles of Prostaglandin D2 Receptors in Ulcerative Colitis

Abstract

Pro-resolution functions were reported for Prostaglandin D2 (PGD2) in colitis, but the role of its two receptors, DP and in particular CRTH2 are less well defined. We investigated DP and CRTH2 expression and function during human and murine ulcerative colitis (UC). Expression of receptors was measured by flow cytometry on peripheral blood leukocytes, and by immunohistochemistry and immunoblotting in colon biopsies of patients with active UC and healthy individuals. Receptor involvement in UC was evaluated in a mouse model of DSS colitis. DP and CRTH2 expression changed in leukocytes of patients with active UC in a differential manner. In UC patients, DP showed higher expression in neutrophils but lower in monocytes as compared to control subjects. In contrast, CRTH2 was decreased in eosinophils, NK and CD3+ T cells but not in monocytes and CD3+/CD4+ T cells. The decrease of CRTH2 on blood eosinophils clearly correlated with disease activity. DP correlated positively with disease activity in eosinophils but inversely in neutrophils. CRTH2 internalized upon treatment with PGD2 and 11-dehydroTXB2 in eosinophils of controls. Biopsies of UC patients revealed an increase of CRTH2-positive cells in the colonic mucosa and high CRTH2 protein content. The CRTH2 antagonist CAY10595 improved while the DP antagonist MK0524 worsened inflammation in murine colitis. DP and CRTH2 play differential roles in UC. Although expression of CRTH2 on blood leukocytes is downregulated in UC, CRTH2 is present in colon tissue where it may contribute to inflammation whereas DP likely promotes anti-inflammatory actions.

Exacerbation of Aging‐Associated and Instability‐Induced Murine Osteoarthritis With Deletion of D Prostanoid Receptor 1, a Prostaglandin D2 Receptor

“…Indeed, DP1 signals through the cAMP/PKA pathway (47) and we have previously shown that DP1 activation inhibits the expression of MMP-1 and MMP-13 in human chondrocytes via the cAMP/PKA pathway (34). This is unlikely, since both receptors usually transmit signals that are antagonistic (25)(26)(27). Therefore, it is possible that down-regulation of the cAMP/PKA pathway mediates, at least partially, the exacerbating effect of DP1 deletion on the progression of OA.…”

“…PGD 2 elicits its downstream effects by activating 2 plasma membrane receptors, D prostanoid receptor 1 (DP1) (8) and chemoattractant receptorlike molecule expressed on Th2 cells (CRTH2), also known as DP2 (9). Activation of DP1 receptors is primarily associated with antiinflammatory effects (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). PGD 2 has also been shown to modulate inflammation, acting as either a proinflammatory or antiinflammatory mediator, depending on the pathologic condition and the affected tissue.…”

“…PGD 2 contributes to multiple physiologic and pathologic processes, including vasodilation (10), platelet aggregation (11), smooth muscle relaxation and contraction (12), sleep/wake regulation (13), mediation of allergic reactions (14), chemotaxis (9), and cell trafficking (15). In contrast, activation of DP2 is generally associated with proinflammatory effects (9,(25)(26)(27)(28)(29)(30)(31)(32)(33). Activation of DP1 receptors is primarily associated with antiinflammatory effects (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27).…”

The endogenous bioactive lipid prostaglandin D 2 ‐glycerol ester reduces murine colitis via DP1 and PPARγ receptors

“…Nonetheless, other studies showed antiinflammatory effects of COX-2, HPGDS, and PGD 2 and its metabolite 15-deoxy-D 12,14 -PGJ 2 (15d-PGJ 2 ) (4,5). In the more specific context of IBD, HPGDS and PGD 2 seem to play an anti-inflammatory role (6,7), although this might be dependent on the receptor activated by PGD 2 because ABBREVIATIONS: 2-AG, 2-arachidonoylglycerol; 15d-PGJ 2 -G, 15-deoxy-D 12,14 -PGJ 2 -G; ABHD6, a/b hydrolase domain 6; ACN, acetonitrile; COX-2, cyclooxygenase-2; DP1/2, prostaglandin D 2 receptor 1/2; DSS, dextran sulfate sodium; HPGDS, hematopoietic prostaglandin D synthase; HTAB, hexadecyltrimethylammonium bromide; IBD, inflammatory bowel disease; MAGL, monoacylglycerol lipase; MMP, matrix metalloproteinase; mPGES1, microsomal prostaglandin E synthase 1; MPO, myeloperoxidase; MRM, multiple reaction monitoring; PG, prostaglandin; PG-EA, prostaglandin-ethanolamide; PG-G, prostaglandin-glycerol ester; PPAR, peroxisome proliferator-activated receptor; qPCR, quantitative PCR; TNBS, trinitrobenzene sulfonic acid PGD 2 receptor 1 (DP1) plays a protective role in experimental colitis, whereas DP2 has a deleterious role (8). On the other hand, the increase in microsomal prostaglandin E synthase 1 (mPGES1) expression that accompanies the increase in COX-2 expression in murine models of IBD pointed to PGE 2 as the culprit in the detrimental effects of COX-2 in colon inflammation.…”

Prostaglandine D2 et homéostasie de la barrière épithéliale intestinale

“…Dans un modèle de colite induite chez le rat, les auteurs décrivent un rôle anti-inflammatoire de la PGD2 lorsqu'elle interagit avec DP1 et, à l'inverse, un rôle pro-inflammatoire quand elle se lie à DP2. Ils observent également une expression différentielle de DP1 et DP2 sur les leucocytes du sang périphérique de patients présentant une rectocolite hémorragique active par rapport aux leucocytes de sujets contrôles [23]. Les aspects mécanistiques ne sont pas encore décryptés ; en effet, les principales lignées cellulaires épithé-liales utilisées dans les études, dérivées d'adénocarcinome colorectal, n'expriment ni DP1 ni DP2 [24], et, à l'heure actuelle, aucune étude du rôle de la PGD2 dans les maladies inflammatoires chroniques de l'intestin n'a été conduite sur des lignées de cellules épithéliales intestinales.…”