Abstract
Prostaglandin D2 (PGD2) acts via the adenyl cyclase-coupled receptor for PGD2 (DP receptor) . Previously, we presented evidence that BW245C, a DP receptor agonist, inhibited chemotaxis, phagocytosis, superoxide anion production and nitrite production, and potentiated TNF-α production by macrophages. To gain information on the mechanism through which agonist of DP receptor potentiated LPS-stimulated TNF-αproduction by macrophages, in this study, we sought to identify downstream effectors of DP receptor-potentiated TNF-αproduction. Both SB203580, a p38 mitogen-activated protein kinase (MAPK) inhibitor, and PD98059, an extracellular signal-related kinase (ERK) 1/2 inhibitor, prevented LPS-induced TNF-αproduction and BW245C-increased TNFαproduction in the presence of LPS, respectively. In contrast, LY294002, a phosphoinositide 3-kinase (PI3K) inhibitor, D609, a phospholipase C (PLC) inhibitor, and suramin, a PLD inhibitor, all did not affect LPS-induced TNF-αproduction, whereas they markedly inhibited BW245C-increased TNFαproduction in the presence of LPS. These results suggest that LPS evidently induced the production of TNF-αthrough p38 MAPK and ERK 1/2 signaling pathways, and that BW245C further increased LPS-induced TNF-αproduction through PI3K, PLC, and PLD.
