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Prostaglandin E₂ Suppresses Lipopolysaccharide-Stimulated IFN-β Production¹

Division of Surgical Research, Department of Surgery, Rhode Island Hospital and Warren Alpert Medical School, Brown University, Providence, RI 02903

Macrophages activate the production of cytokines and chemokines in response to LPS through signaling cascades downstream from TLR4. Lipid mediators such as PGE₂, 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 PGE₂ 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 PGE₂ strongly suppresses LPS-induced IFN-β production at the mRNA and protein levels. Poly (I:C)-induced IFN-β and LPS-induced CCL5 production were also suppressed by PGE₂. The inhibitory effect of PGE₂ on LPS-induced IFN-β expression is mediated through PGE₂ receptor subtypes EP₂ and EP₄, 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 GSK3β. In contrast, PGE₂ inhibits LPS-induced TNF- 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-β concentration in mice. Collectively, data demonstrate that PGE₂ is a negative regulator for IFN-β production in activated macrophages and during endotoxemia.

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¹ This work was supported by National Institutes of Health Grant GM-42859 (to J.E.A).

² Address correspondence and reprint requests to Dr. X. Julia Xu, Department of Surgery, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903. E-mail address: Julia_Xu{at}brown.edu

³ Abbreviations used in this paper: COX, cyclooxygenase; PKA, protein kinase A; Epac, exchange protein directly activated by cAMP; EP, E prostanoid receptor.

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