Regulation of TNFα and interleukin-10 production by prostaglandins I2 and E2:: studies with prostaglandin receptor-deficient mice and prostaglandin E-receptor subtype-selective synthetic agonists

To know which receptors of prostaglandins are involved in the regulation of TNF alpha and interleukin 10 (IL-10) production, we examined the production of these cytokines in murine peritoneal macrophages stimulated with zymosan. The presence of PGE, or the PGI, analog carbacyclin in the medium reduced the TNF alpha production to one-half, whereas IL-10 production increased several fold; and indomethacin caused the reverse effects, suggesting that endogenous prostaglandins may have a regulatory effect on the cytokine production. Among prostaglandin E (EP) receptor-selective synthetic agonists, EP2 and EP4 agonists caused down-regulation of the zymosan-induced TNF alpha production, but up-regulation on the IL-IO production; while EP1 and EP3 agonists showed no effect. Macrophages harvested from prostaglandin I (IP) receptor-deficient mice showed the up- and down-regulatory effects on the cytokine production by the EP2 and EP4 agonists or PGE(2), but no effect was obtained by carbacyclin. On the contrary, macrophages from EP2-deficient mice showed the effect by PGE(2), carbacyclin, and the EP4 agonist, but not by the EP2 agonist; and the cells from EP4-deficient mice showed the effect by PGE,, carbacyclin, and EP2 agonist, but not by the EP3 agonist. These functional effects of prostaglandins well accorded with the mRNA expression of TNF alpha and IL-10 when such expression was examined by the RT-PCR method. The peritoneal macrophages from normal mice expressed IF, EP2, and EP4 receptors, but not EPI and EP3, when examined by RT-PCR. Thus the results suggest that PGI, and PGE, generated simultaneously with cytokines by macrophages treated with zymosan may influence the cytokine production through IF, EP2, and EP4 receptors. (C) 2001 Elsevier Science Inc. All rights reserved.