PROSTAGLANDIN I-2 ANALOG, ILOPROST, DOWN-REGULATES MITOGEN-ACTIVATED PROTEIN-KINASES OF MACROPHAGES

Objective. Vascular endothelial cells (EC) play a pivotal role in diff use organ injury seen in ARDS and MOFS. On exposure to cytokines or en dotoxin (LPS), EC are stimulated to express adhesion molecules as well as proinflammatory and procoagulant activity. However, the potential feedback control df EC on macrophages (M phi) is not clear. We studied the cellular mechanism of iloprost, a PGI(2) analogue, in regulation of TNF production by LPS-stimulated M phi Methods. Rabbit alveolar M p hi and mouse M phi RAW 264.7 cells were exposed to Escherichia coli LP S in the presence of various concentrations of iloprost. TNF productio n was measured by L929 bioassays, To further study the cellular mechan ism of iloprost on M phi activation, RAW 264.7 cells were stimulated b y LPS (10 mu g/ml) in the presence of either iloprost or specific mito gen-activated protein kinase (MAPK) inhibitors, either PD98059 or SB20 2190. P44/P42 and P38 MAPK activation were evaluated by Western blot a ssays with anti-phospho MAPK antibodies. Results. LPS induced M phi TN F production, which was inhibited by iloprost. Iloprost also attenuate d the activation of P44/P42 and P38 induced by LPS. Inhibition of P44/ P42 with PD98059 or P38 with SB202190 significantly reduced TNF produc tion by LPS-stimulated RAW cells. Conclusions. The regulatory mechanis m of EC on M phi, activation is dependent on PGI2. The effect of PGI, on M phi is, at least in part, mediated through inhibiting MAPKs. (C) 1998 Academic Press.