The roles of the prostaglandin D(2) receptors DP(1) and CRTH2 in promoting allergic responses

Abstract

Prostaglandin D(2) (PGD(2)) is produced by mast cells, Th2 lymphocytes and dendritic cells and has been detected in high concentrations at sites of allergic inflammation. PGD(2) exerts its inflammatory effects through high affinity interactions with the G protein coupled receptors DP(1) and chemoattractant-homologous receptor expressed on Th2 cells (CRTH2, also known as DP(2)). DP(1) and CRTH2 act in concert to promote a number of biological effects associated with the development and maintenance of the allergic response. During the process of allergen sensitization, DP(1) activation may enhance polarization of Th0 cells to Th2 cells by inhibiting production of interleukin 12 by dendritic cells. Upon exposure to allergen in sensitized individuals, activation of DP(1) may contribute to the long lasting blood flow changes in the target organ. CRTH2 is expressed by Th2 lymphocytes, eosinophils and basophils and may mediate the recruitment of these cell types during the late phase allergic response. The role played by CRTH2 in promoting the production of Th2 cytokines and IgE make antagonism of this receptor a particularly attractive approach to the treatment of chronic allergic disease.

Figure 1

Development of an early- and late-phase airway response in response to allergen in a sensitized individual. The early phase fall in lung function is due to mast cell-dependent bronchospasm, mediated largely by leukotrienes. The late-phase response is mediated by activated Th2 cells and suppressed by drugs that inhibit T-cell function such as steroids and cyclosporine. It is proposed that CRTH2 is involved in both mast cell-mediated activation of Th2 cells and the amplification of Th2 recruitment that occurs as a result of IgE-facilitated antigen presentation by airway dendritic cells.

Figure 2

Effect of a selective CRTH2 antagonist on airway inflammation 24 h after challenge with antigen in sensitized guinea pigs. The drug was dosed by oral gavage 1 h before and 12 h after allergen exposure. Data are presented as the mean±s.e.mean (n=10 animals per group, ^*P<0.01 compared to vehicle control).

Figure 3

Proposed scheme whereby the combined action of DP₁ and CRTH2 leads to the polarization and activation of Th2 lymphocytes. PGD₂ derived from mast cells acts on dendritic cells to inhibit production of interleukin 12 by an action on DP₁ and thereby creates an environment where T cells are polarized to the Th2 phenotype. Thymic stromal lymphopoietin also acts on dendritic cells to promote Th2 polarization, an effect associated with induction of PGD₂ synthase. CRTH2 contributes both to mast cell-dependent activation of Th2 cells and eosinophils and to paracrine activation of Th2 cells as might occur during IgE-facilitated antigen presentation.