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The inducible cyclooxygenase (COX), COX-2, mediates a significant component of this response in brain via downstream proinflammatory PG signaling. In this study, we investigated the function of the PGE2 E-prostanoid (EP) 4 receptor in the CNS innate immune response to the bacterial endotoxin LPS. We report that PGE2 EP4 signaling mediates an anti-inflammatory effect in brain by blocking LPS-induced proinflammatory gene expression in mice. This was associated in cultured murine microglial cells with decreased Akt and I-\u03baB kinase phosphorylation and decreased nuclear translocation of p65 and p50 NF-\u03baB subunits. In vivo, conditional deletion of EP4 in macrophages and microglia increased lipid peroxidation and proinflammatory gene expression in brain and in isolated adult microglia following peripheral LPS administration. Conversely, EP4 selective agonist decreased LPS-induced proinflammatory gene expression in hippocampus and in isolated adult microglia. In plasma, EP4 agonist significantly reduced levels of proinflammatory cytokines and chemokines, indicating that peripheral EP4 activation protects the brain from systemic inflammation. The innate immune response is an important component of disease progression in a number of neurodegenerative disorders, such as Alzheimer\u2019s disease, Parkinson\u2019s disease, and amyotrophic lateral sclerosis. In addition, recent studies demonstrated adverse vascular effects with chronic administration of COX-2 inhibitors, indicating that specific PG signaling pathways may be protective in vascular function. This study supports an analogous and beneficial effect of PGE2 EP4 receptor signaling in suppressing brain inflammation.<\/jats:p>","DOI":"10.4049\/jimmunol.0903487","type":"journal-article","created":{"date-parts":[[2010,5,7]],"date-time":"2010-05-07T22:34:55Z","timestamp":1273271695000},"page":"7207-7218","source":"Crossref","is-referenced-by-count":140,"title":["The Prostaglandin E2 E-Prostanoid 4 Receptor Exerts Anti-Inflammatory Effects in Brain Innate Immunity"],"prefix":"10.1093","volume":"184","author":[{"given":"Ju","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny","family":"Johansson","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel S","family":"Woodling","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J","family":"Montine","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Washington , Seattle, WA 98104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Andreasson","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2010,6,15]]},"reference":[{"key":"2026012806331864800_r1","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/nrn752","article-title":"Innate immunity: the missing link in neuroprotection and neurodegeneration?","volume":"3","author":"Nguyen","year":"2002","journal-title":"Natl. 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