Prostaglandin E2 suppresses LPS-stimulated IFNβ 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 ma...

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Published in:The Journal of immunology (1950) 2008-02, Vol.180 (4), p.2125-2131
Main Authors: Julia Xu, X., Reichner, Jonathan S., Mastrofrancesco, Balduino, Henry, William L., Albina, Jorge E.
Format: Article
Language:English
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Summary: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 effect. We demonstrate that PGE 2 strongly suppresses LPS-induced IFNβ production at the mRNA and protein levels. Poly I:C-induced IFNβ and LPS-induced CCL5 production were also suppressed by PGE 2 . The inhibitory effect of PGE 2 on LPS-induced IFNβ expression is mediated through PGE 2 receptor subtypes EP 2 and EP 4 , and mimicked by the cAMP analogue 8-Br-cAMP as well as by the adenylyl cyclase activator forskolin. The downstream effector molecule responsible for the cAMP-induced suppressive effect is Epac but not PKA. Moreover, data demonstrate that Epac-mediated signaling proceeds through PI3K, Akt, and GSK3β. In contrast, PGE 2 inhibits LPS-induced TNFα production in these cells through a distinct pathway requiring PKA activity and independent of Epac/PI3K/Akt. In vivo , administration of a COX inhibitor prior to LPS injection resulted in enhanced serum IFNβ concentration in mice. Collectively, data demonstrate that PGE 2 is a negative regulator for IFNβ production in activated macrophages and during endotoxemia.
ISSN:0022-1767
1550-6606