Prostaglandin D2 Induces IL-8 and GM-CSF by Bronchial Epithelial Cells in a CRTH2-Independent Pathway

Abstract

Background: Prostaglandin D₂ (PGD₂), a major prostanoid produced by activated mast cells, has long been implicated in allergic diseases. PGD₂ demonstrates its effects through two G-protein-coupled receptors, DP and CRTH2. The PGD₂/CRTH2 system mediates chemotaxis of eosinophils, basophils, and Th2 cells, which are involved in the induction of allergic inflammation. Although recent studies have shown that the specific receptors for PGD₂, DP, and CRTH2 are expressed in various human tissues, the role of PGD₂ is unknown in human bronchial epithelial cells. In this study, we investigated the expression and function of CRTH2/DP on NCI-H₂₉₂ and NHBE cells. Method: The CRTH2/DP expression was examined by RT-PCR and flow-cytometric analysis. NCI-H₂₉₂ and NHBE cells were cultured in the presence of various stimulants. The resulting supernatants were measured by ELISA. Results: We demonstrated that PGD₂ induced production of IL-8 and GM-CSF in NCI-H₂₉₂ and NHBE cells. DK-PGD₂ (CRTH2 agonist) and latanoprost (FP, a prostaglandin F receptor, agonist) failed to augment the production of these cytokines. Pretreatment with ramatroban (CRTH2 antagonist) and AL8810 (FP antagonist) did not reduce the production of these cytokines. The PGD₂-induced cytokine production was inhibited by pertussis toxin or specific inhibitors for MAP/ERK kinase (PD98059) and p38 MAP kinase (SB202190). Conclusion: These results suggest that PGD₂ is a potent inducer of IL-8 and GM-CSF production with MAP/ERK and p38 MAP kinase activation, but this is independent of CRTH2 activation.