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 (interleukin)-10 in the crossregulation of prostaglandins and cytokines in human monocytes. We first determined the effects of tumor necrosis factor-alpha (TNF-alpha) and IL-10 on monocyte prostaglandin E-2 (PGE(2)) production. Unstimulated monocytes constitutively produced a small but significant amount of PGE(2) in the culture supernatants. Both TNF-alpha and lipopolysaccharide (LPS) caused a remarkable increase in monocyte PGE(2) production. On the other hand, IL-10 alone was without effect on constitutive PGE(2) production but drastically inhibited LPS-induced PGE(2) production in monocytes. Moreover, this inhibitory effect of IL-10 was not simply attributable to its inhibition of TNF-alpha production in LPS-stimulated monocytes. Next, we determined the effect of PGE(2) on TNF-alpha mRNA expression in monocytes. Treatment of monocytes with or without PGE(2) showed no detectable TNF-alpha mRNA. Activation of monocytes by LPS resulted in a remarkable accumulation of TNF-alpha mRNA and PGE(2) efficiently inhibited this expression. Finally, we determined the effect of PGE(2) on IL-10 mRNA expression in monocytes. Similar to TNF-alpha mRNA, unstimulated monocytes showed no detectable 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 expression. 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, plays a crucial role in terminating the inflammatory cascade via downregulation of production of proinflammatory molecules including TNF-alpha and PGE(2).