Regulation of TNF alpha and interleukin-10 production by prostaglandins I-2 and E-2: 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 productio n of these cytokines in murine peritoneal macrophages stimulated with zymos an. The presence of PGE, or the PGI, analog carbacyclin in the medium reduc ed 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 pro duction. Among prostaglandin E (EP) receptor-selective synthetic agonists, EP2 and EP4 agonists caused down-regulation of the zymosan-induced TNF alph a 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 c ytokine production by the EP2 and EP4 agonists or PGE(2), but no effect was obtained by carbacyclin. On the contrary, macrophages from EP2-deficient m ice 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 f unctional effects of prostaglandins well accorded with the mRNA expression of TNF alpha and IL-10 when such expression was examined by the RT-PCR meth od. 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 s uggest that PGI, and PGE, generated simultaneously with cytokines by macrop hages treated with zymosan may influence the cytokine production through IF , EP2, and EP4 receptors. (C) 2001 Elsevier Science Inc. All rights reserve d.