Differential Roles of PKA and Epac on the Production of Cytokines in the Endotoxin-Stimulated Primary Cultured Microglia

Author： Liu Jian Zhao Xin Cao Jianping Xue Qingsheng Feng Xiaomei Liu Xuesheng Zhang Fujun Yu Buwei

Publisher： Humana Press, Inc

ISSN： 0895-8696

Source： Journal of Molecular Neuroscience, Vol.45, Iss.2, 2011-10, pp. : 186-193

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Abstract

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.