Journal
GLIA
Volume 55, Issue 2, Pages 214-223Publisher
WILEY-LISS
DOI: 10.1002/glia.20453
Keywords
prostaglandin E-2; p38MAPK; calcium; proinflammatory mediators; cAMP; inducible nitric oxide synthase; IFN-alpha
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Astrocytes, the most abundant glia in the central nervous system (CNS), produce a large amount of prostaglandin E-2 (PGE(2)) in response to proinflammatory mediators after CNS injury. However, it is unclear whether PGE2 has a regulatory role in astrocytic activity under the inflamed condition. In the present work, we showed that PGE2 increased inducible nitric oxide synthase (iNOS) production by tumor necrosis factor-et and interferon-gamma (T/I) in astrocytes. Pharmacological and RNA interference approaches further indicated the involvement of the receptor EP2 in PGE(2)-induced iNOS upregulation in T/I-treated astrocytes. Quantitative real-time polymerase chain reaction and gel mobility shift assays also demonstrated that PGE2 increased iNOS transcription through EP2-induced cAMP/protein kinase A (PYA)-dependent pathway. Consistently, the effect of EP2 was significantly attenuated by the PKA inhibitor KT-5720 and partially suppressed by the inhibitor (SB203580) of p38 mitogen-activated protein kinase (p38MAPK), which serves as one of the downstream components of the PKA-dependent pathway. Interestingly, EP2-mediated PKA signaling appeared to increase intracellular Ca2+ release through inositol triphosphate (IP3) receptor activation, which might in turn stimulate protein kinase C (PKC) activation to promote iNOS production in T/I-primed astrocytes. By analyzing the expression of astrocytic glial fibrillary acidic protein (GFAP), we found that PGE(2) alone only triggered the EP2-induced cAMP/PKA/p38MAPK signaling pathway in astrocytes. Collectively, PGE2 may enhance T/I-induced astrocytic activation by augmenting iNOS/NO production through EP2-mediated cross-talk between cAMP/PKA and IP3/Ca2+ signaling pathways. (c) 2006 Wiley-Liss, Inc.
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