Prostaglandin E2 Suppresses Lipopolysaccharide-Stimulated IFN- Production

Macrophages activate the production of cytokines and chemokines in response to LPS through signaling cascades downstream from TLR4. Lipid mediators such as PGE 2 , which are produced during inflammatory responses, have been shown to suppress MyD88-dependent gene expression upon TLR4 activation in macrophages. The study reported here investigated the effect of PGE 2 on TLR3- and TLR4-dependent, MyD88-independent gene expression in murine J774A.1 macrophages, as well as the molecular mechanism underlying such an effect. We demonstrate that PGE 2 strongly suppresses LPS-induced IFN- (cid:1) production at the mRNA and protein levels. Poly (I:C)-induced IFN- (cid:1) and LPS-induced CCL5 production were also suppressed by PGE 2 . The inhibitory effect of PGE 2 on LPS-induced IFN- (cid:1) expression is mediated through PGE 2 receptor subtypes EP 2 and EP 4 , and mimicked by the cAMP analog 8-Br-cAMP as well as by the adenylyl cyclase activator forskolin. The downstream effector molecule responsible for the cAMP-induced suppressive effect is exchange protein directly activated by cAMP (Epac) but not protein kinase A. Moreover, data demonstrate that Epac-mediated signaling proceeds through PI3K, Akt, and GSK3 (cid:1) . In contrast, PGE 2 inhibits LPS-induced TNF- (cid:2) production in these cells through a distinct pathway requiring protein kinase A activity and independent of Epac/PI3K/Akt. In vivo, administration of a cyclooxygenase inhibitor before LPS injection resulted in enhanced serum IFN- (cid:1) concentration in mice. Collectively, data demonstrate that PGE 2 is a negative regulator for IFN- (cid:1) production in activated macrophages P40, protease inhibitor Applied blot (cid:3) ni-trocellulose

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