Journal
JOURNAL OF MOLECULAR NEUROSCIENCE
Volume 45, Issue 2, Pages 186-193Publisher
HUMANA PRESS INC
DOI: 10.1007/s12031-010-9426-x
Keywords
Microglia; Protein kinase A; cAMP-responsive guanine nucleotide exchange factor; Mitogen-activated protein kinases p38; Glycogen synthase kinase-3 beta
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Funding
- National Natural Science Foundation of China [30600583, 30901399]
- National Postdoctoral Science Foundation of China [20080440625]
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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-3 beta (GSK-3 beta) 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-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) 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-alpha expression. Western blots assays indicated that 6-Bnz-cAMP significantly inhibited lipopolysaccharide-induced activation of both p38 and GSK-3 beta in a dose-dependent manner; in contrast, 8-pCPT-2'-O-Me-cAMP only slightly repressed GSK-3 beta 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-alpha, IL-1 beta, and IL-10, possibly owing to the different effects on the downstream effectors, MAPK p38, and GSK-3 beta.
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