Prostaglandin D2 Causes Preferential Induction of Proinflammatory Th2 Cytokine Production through an Action on Chemoattractant Receptor-Like Molecule Expressed on Th2 Cells

Abstract

PGD2, produced by mast cells, has been detected in high concentrations at sites of allergic inflammation. It can stimulate vascular and other inflammatory responses by interaction with D prostanoid receptor (DP) and chemoattractant receptor-like molecule expressed on Th2 cells (CRTH2) receptors. A significant role for PGD2 in mediating allergic responses has been suggested based on the observation that enhanced eosinophilic lung inflammation and cytokine production is apparent in the allergen-challenged airways of transgenic mice overexpressing human PGD2 synthase, and PGD2 can enhance Th2 cytokine production in vitro from CD3/CD28-costimulated Th2 cells. In the present study, we investigated whether PGD2 has the ability to stimulate Th2 cytokine production in the absence of costimulation. At concentrations found at sites of allergic inflammation, PGD2 preferentially elicited the production of IL-4, IL-5, and IL-13 by human Th2 cells in a dose-dependent manner without affecting the level of the anti-inflammatory cytokine IL-10. Gene transcription peaked within 2 h, and protein release peaked ∼8 h after stimulation. The effect of PGD2 was mimicked by the selective CRTH2 agonist 13,14-dihydro-15-keto-PGD2 but not by the selective DP agonist BW245C, suggesting that the stimulation is mediated by CRTH2 and not DP. Ramatroban, a dual CRTH2/thromboxane-like prostanoid receptor antagonist, markedly inhibited Th2 cytokine production induced by PGD2, while the selective thromboxane-like prostanoid receptor antagonist SQ29548 was without effect. These data suggest that PGD2 preferentially up-regulates proinflammatory cytokine production in human Th2 cells through a CRTH2-dependent mechanism in the absence of any other costimulation and highlight the potential utility of CRTH2 antagonists in the treatment of allergic diseases.

T cell polarization identifies distinct clinical phenotypes in scleroderma lung disease

“…The polarization of circulating T cells in patients with SSc and healthy control subjects was determined using very specific type 1 (Th1/Tc1) or type 2 (Th2/Tc2) surface markers. The chemokine receptor CCR5 has been previously described as an exclusive marker of Th1 cells, while the prostaglandin D 2 receptor DP2 (CD294), also referred to as chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2), recently emerged as a consistent, predictive marker of Th2 cell function in basic and translational studies (30)(31)(32).…”

Immunomodulatory mast cells: negative, as well as positive, regulators of immunity

“…Mast cells represent potential sources of many mediators that can enhance or suppress the development, survival, proliferation, migration, maturation, or function of immune cells (reviewed in REFS [1][2][3][5][6][7][8]13,[16][17][18]21,30,31,43,44,[46][47][48][49][50][51][52][53][54][55][56]. Some individual mediators, such as histamine, can have both positive and negative immunomodulatory effects.…”

The Role of the Prostaglandin D2 Receptor, DP, in Eosinophil Trafficking

“…In addition, CRTH2 is activated by several PGD 2 metabolites, including 13,14-dihydro-15-keto-(DK)-PGD 2 , PGJ 2 , ⌬ 12 PGJ 2 , and 15-deoxy-PGJ 2 (7,8) and a thromboxane (TX) metabolite, 11-dehydro-TXB 2 (9). Moreover, CRTH2 mediates the respiratory burst and degranulation of eosinophils (8,10), induces the production of proinflammatory cytokines in Th2 cells (11), and enhances the release of histamine from basophils (12). In humans, CRTH2 is the most reliable marker for Th2 cells (13), and in animal models, CRTH2 mediates eosinophil infiltration into the lungs and skin and aggravates the pathology of allergic responses (14 -16).…”