Prostaglandin D<sub>2</sub> Induces IL-8 and GM-CSF by Bronchial Epithelial Cells in a CRTH2-Independent Pathway

Abstract

<i>Background:</i> Prostaglandin D<sub>2</sub> (PGD<sub>2</sub>), a major prostanoid produced by activated mast cells, has long been implicated in allergic diseases. PGD<sub>2</sub> demonstrates its effects through two G-protein-coupled receptors, DP and CRTH2. The PGD<sub>2</sub>/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 PGD<sub>2</sub>, DP, and CRTH2 are expressed in various human tissues, the role of PGD<sub>2</sub> is unknown in human bronchial epithelial cells. In this study, we investigated the expression and function of CRTH2/DP on NCI-H<sub>292</sub> and NHBE cells. <i>Method:</i> The CRTH2/DP expression was examined by RT-PCR and flow-cytometric analysis. NCI-H<sub>292</sub> and NHBE cells were cultured in the presence of various stimulants. The resulting supernatants were measured by ELISA. <i>Results:</i> We demonstrated that PGD<sub>2</sub> induced production of IL-8 and GM-CSF in NCI-H<sub>292</sub> and NHBE cells. DK-PGD<sub>2</sub> (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 PGD<sub>2</sub>-induced cytokine production was inhibited by pertussis toxin or specific inhibitors for MAP/ERK kinase (PD98059) and p38 MAP kinase (SB202190). <i>Conclusion:</i> These results suggest that PGD<sub>2</sub> 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.