ROLE OF IL-10 IN THE CROSSREGULATION OF PROSTAGLANDINS AND CYTOKINES IN MONOCYTES

In the present study we have focused mainly on the role of IL (interle ukin)-10 in the crossregulation of prostaglandins and cytokines in hum an monocytes. We first determined the effects of tumor necrosis factor -alpha (TNF-alpha) and IL-10 on monocyte prostaglandin E-2 (PGE(2)) pr oduction. Unstimulated monocytes constitutively produced a small but s ignificant amount of PGE(2) in the culture supernatants. Both TNF-alph a and lipopolysaccharide (LPS) caused a remarkable increase in monocyt e PGE(2) production. On the other hand, IL-10 alone was without effect on constitutive PGE(2) production but drastically inhibited LPS-induc ed PGE(2) production in monocytes. Moreover, this inhibitory effect of IL-10 was not simply attributable to its inhibition of TNF-alpha prod uction in LPS-stimulated monocytes. Next, we determined the effect of PGE(2) on TNF-alpha mRNA expression in monocytes. Treatment of monocyt es with or without PGE(2) showed no detectable TNF-alpha mRNA. Activat ion of monocytes by LPS resulted in a remarkable accumulation of TNF-a lpha mRNA and PGE(2) efficiently inhibited this expression. Finally, w e determined the effect of PGE(2) on IL-10 mRNA expression in monocyte s. Similar to TNF-alpha mRNA, unstimulated monocytes showed no detecta ble IL-10 mRNA. Interestingly, PGE(2) alone drastically induced IL-10 mRNA. Besides, activation of monocytes by LPS resulted in a remarkable accumulation of IL-10 mRNA, and PGE(2) further enhanced this expressi on. These results indicate that TNF-alpha and PGE(2) are key molecules for the induction of IL-10 in monocytes, and that IL-10, in turn, pla ys a crucial role in terminating the inflammatory cascade via downregu lation of production of proinflammatory molecules including TNF-alpha and PGE(2).