MAP KINASE PATHWAYS AS A ROUTE FOR REGULATORY MECHANISMS OF IL-10 ANDIL-4 WHICH INHIBIT COX-2 EXPRESSION IN HUMAN MONOCYTES

Mitogen-activated protein kinases (MAPKs) are activated by various ext racellular stimuli and play an important role in regulating the expres sion of proinflammatory molecules in monocytes/macrophages. We first q uestioned whether MAPK activation is involved in cyclooxygenase (COX)- 2 expression in lipopolysaccharide (LPS)-stimulated human monocytes. L PS induced the expression of COX-2 protein and COX-2 mRNA as well as t he phosphorylation and activation of extracellular signal-regulated pr otein kinase (ERK)2 and p38 MAPK in monocytes. The induction of COX-2 mRNA, COX-2 protein, and prostaglandin (PG)E-2 by LPS was inhibited by the specific inhibitors of ERK and p38 MAPK, suggesting that the acti vation of ERK2 and p38 MAPK is involved in COX-2 expression in LPS-sti mulated monocytes. Since we previously showed that interleukin (IL)-10 and IL-4 similarly inhibited COX-2 expression in LPS-stimulated monoc ytes, we next questioned whether these cytokines regulate the phosphor ylation and activation of ERK2 and p38 MAPK in LPS-stimulated monocyte s. Interestingly, LPS-induced phosphorylation and activation of ERK2 w as significantly inhibited by IL-4 and IL-10, while that of p38 MAPK w as inhibited by IL-10, but not IL-4. These results suggest that the me chanisms of inhibition by IL-10 and IL-4 of the LPS-induced expression of proinflammatory molecules could be ascribed to the regulatory effe cts of both cytokines on MAPK activation. (C) 1998 Academic Press.