The Expression of Prostaglandin E Receptors EP2 and EP4 and Their Different Regulation by Lipopolysaccharide in C3H/HeN Peritoneal Macrophages

Abstract

The expression and regulation of the PGE receptors, EP2 and EP4, both of which are coupled to the stimulation of adenylate cyclase, were examined in peritoneal resident macrophages from C3H/HeN mice. mRNA expression of EP4 but not EP2 was found in nonstimulated cells, but the latter was induced by medium change alone, and this induction was augmented by LPS. mRNA expression of EP4 was down-regulated by LPS but not by medium change. PGE2 increased the cAMP content of both LPS-treated and nontreated cells. ONO-604, an EP4 agonist, also increased cAMP content in nonstimulated cells and in cells treated with LPS for 3 h, but not for 6 h. Butaprost, an EP2 agonist, was effective only in the cells treated with LPS for 6 h. The inhibitory effects of ONO-604 on TNF-α and IL-12 production were equipotent with PGE2 at any time point, but the inhibitory effects of butaprost were only seen from 14 h after stimulation. PGE2 or dibutyryl cAMP alone, but not butaprost, reduced EP4 expression, and indomethacin reversed the LPS-induced down-regulation of EP4, indicating that the down-regulation of EP4 is mediated by LPS-induced PG synthesis and EP4 activation. Indeed, when we used C3H/HeJ (LPS-hyporesponsive) macrophages, such reduction in EP4 expression was found in the cells treated with PGE2 alone, but not in LPS-treated cells. In contrast, up-regulation of EP2 expression was again observed in LPS-treated C3H/HeJ macrophages. These results suggest that EP4 is involved mainly in the inhibition of cytokine release, and that the gene expression of EP2 and EP4 is differentially regulated during macrophage activation.

Prostaglandin E2 Mediates IL-1β-Related Fibroblast Mitogenic Effects in Acute Lung Injury through Differential Utilization of Prostanoid Receptors

“…Alternatively, relative overexpression of EP3 over EP2 may favor an EP3-type response to lower concentrations of PGE 2 . Changes in EP receptor expression profiles can be mediated by several factors known to be increased in ALI including LPS, serum, stress, and IFN-␥, and PGE 2 itself (33,63,64). In fact, fibroblasts isolated from wild-type mice after experimentally induced lung fibrosis exhibit a relative increase in the proportion of EP3 over EP2 receptors, and a switch from a proliferative-suppressive to a proliferative-stimulating response to PGE 2 (36).…”

Lipopolysaccharide-Dependent Prostaglandin E2 Production Is Regulated by the Glutathione-Dependent Prostaglandin E2 Synthase Gene Induced by the Toll-Like Receptor 4/MyD88/NF-IL6 Pathway

“…There are several reports that PGE 2 contributes to immune suppression and that PGE 2 secreted from activated macrophages in response to proinflammatory stimuli acts on the macrophages themselves and exhibits an inhibitory function in a negative feedback loop (21). Addition of exogenous PGE 2 has been shown to reduce LPS-induced IL-6 and TNF-␣ production, but not IL-1␤ production, in macrophages (31).…”

“…PGE 2 has been shown to modulate the production of proinflammatory cytokines (21). Therefore, we analyzed the LPS-induced production of proinflammatory cytokines in mPGES-mutant mice.…”

Prostaglandin E2 Protects Gastric Mucosal Cells from Apoptosis via EP2 and EP4 Receptor Activation

“…We consider that this experiment cannot exclude the possibility that EP 2 is weakly expressed in gastric mucosal cells, because it was recently reported (39) that EP 2 is expressed in the stomach of the mouse, using RNase protection assay. Furthermore, it was recently found that the gene encoding EP 2 is inducible in macrophages; EP 2 mRNA was detected only after a change of medium or following the addition of LPS to the medium (41). Therefore, it is also possible that an unknown stimulus under our culture conditions induces EP 2 mRNA expression.…”