Prostaglandin E2 Suppresses Lipopolysaccharide-Stimulated IFN-β Production
| Autor: | Jonathan S. Reichner, Jorge E. Albina, X. Julia Xu, Balduino Mastrofrancesco, William L. Henry |
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| Rok vydání: | 2008 |
| Předmět: |
Lipopolysaccharides
Male medicine.medical_specialty Immunology Dose-Response Relationship Immunologic Biology Dinoprostone Article Cell Line Adenylyl cyclase Mice chemistry.chemical_compound Internal medicine medicine Animals Immunology and Allergy RNA Messenger Protein kinase A Protein kinase B PI3K/AKT/mTOR pathway Forskolin Macrophages Interferon-beta Lipid signaling Macrophage Activation Endotoxemia Cell biology Endocrinology Gene Expression Regulation chemistry Myeloid Differentiation Factor 88 TLR4 lipids (amino acids peptides and proteins) Signal transduction Signal Transduction |
| Zdroj: | The Journal of Immunology. 180:2125-2131 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | 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-α 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. |
| Databáze: | OpenAIRE |
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