Differential Roles of PKA and Epac on the Production of Cytokines in the Endotoxin-Stimulated Primary Cultured Microglia
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- 作者：Jian Liu (1)
Xin Zhao (1)
Jianping Cao (2)
Qingsheng Xue (1)
Xiaomei Feng (1)
Xuesheng Liu (1)
Fujun Zhang (1)
Buwei Yu (1) - 关键词：Microglia ; Protein kinase A ; cAMP ; responsive guanine nucleotide exchange factor ; Mitogen ; activated protein kinases p38 ; Glycogen synthase kinase ; 3β
- 刊名：Journal of Molecular Neuroscience
- 出版年：2011
- 出版时间：October 2011
- 年：2011
- 卷：45
- 期：2
- 页码：186-193
- 全文大小：391KB
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Xin Zhao (1)
Jianping Cao (2)
Qingsheng Xue (1)
Xiaomei Feng (1)
Xuesheng Liu (1)
Fujun Zhang (1)
Buwei Yu (1)
1. Department of Anesthesiology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 197 Ruijin Er Road, Shanghai, 200025, People’s Republic of China
2. Department of Anesthesiology, PLA 455th Hospital, 338 West Huaihai Road, Shanghai, 200052, People’s Republic of China
文摘
To further understand the anti-inflammatory effect of adenosine cyclic 3-5-monophosphate (cAMP), we examined the effect of protein kinase A (PKA) and cAMP-responsive guanine nucleotide exchange factor (Epac) on the transcription and production of cytokines and on the activity of mitogen-activated protein kinases (MAPK) p38 and glycogen synthase kinase-3β (GSK-3β) in endotoxin-treated rat primary cultured microglia. The PKA specific agonist N6-benzoyladenosine-3,5-cAMP (6-Bnz-cAMP) not only inhibited the transcription and production of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) but also enhanced the transcription and expression of IL-10, while the Epac selective analog 8-(4-chlorophenylthio)-2-O-methyladenosine-3,5-cAMP (8-pCPT-2-O-Me-cAMP) merely repressed the TNF-α expression. Western blots assays indicated that 6-Bnz-cAMP significantly inhibited lipopolysaccharide-induced activation of both p38 and GSK-3β in a dose-dependent manner; in contrast, 8-pCPT-2-O-Me-cAMP only slightly repressed GSK-3β activity at large doses. Pretreatment with H-89, a specific PKA antagonist, could completely reverse the effect of 6-Bnz-cAMP on cytokines expressions and kinases activities but had no effect on the performance of 8-pCPT-2-O-Me-cAMP. Our findings indicate that PKA and Epac exert differential effect on the expression of inflammatory cytokines such as TNF-α, IL-1β, and IL-10, possibly owing to the different effects on the downstream effectors, MAPK p38, and GSK-3β.