TNF-α/IFN-γ-induced iNOS expression increased by prostaglandin E2 in rat primary astrocytes via EP2-evoked cAMP/PKA and intracellular calcium signaling
✍ Scribed by Han-Yun Hsiao; Oi-Tong Mak; Chung-Shi Yang; Yu-Peng Liu; Kuan-Ming Fang; Shun-Fen Tzeng
- Book ID
- 102223477
- Publisher
- John Wiley and Sons
- Year
- 2006
- Tongue
- English
- Weight
- 495 KB
- Volume
- 55
- Category
- Article
- ISSN
- 0894-1491
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✦ Synopsis
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 PGE 2 has a regulatory role in astrocytic activity under the inflamed condition. In the present work, we showed that PGE 2 increased inducible nitric oxide synthase (iNOS) production by tumor necrosis factor-a and interferon-g (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 PGE 2 increased iNOS transcription through EP2-induced cAMP/protein kinase A (PKA)-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 Ca 21 release through inositol triphosphate (IP3) receptor activation, which might in turn stimulate protein kinase C (PKC) activation to promote iNOS production in T/Iprimed 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, PGE 2 may enhance T/I-induced astrocytic activation by augmenting iNOS/NO production through EP2-mediated cross-talk between cAMP/PKA and IP3/Ca 21 signaling pathways. V