Journal of Molecular Neuroscience

, Volume 45, Issue 2, pp 186–193 | Cite as

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

  • Jian Liu
  • Xin Zhao
  • Jianping Cao
  • Qingsheng Xue
  • Xiaomei Feng
  • Xuesheng Liu
  • Fujun Zhang
  • Buwei Yu
Article

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.

Keywords

Microglia Protein kinase A cAMP-responsive guanine nucleotide exchange factor Mitogen-activated protein kinases p38 Glycogen synthase kinase-3β 

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Jian Liu
    • 1
  • Xin Zhao
    • 1
  • Jianping Cao
    • 2
  • Qingsheng Xue
    • 1
  • Xiaomei Feng
    • 1
  • Xuesheng Liu
    • 1
  • Fujun Zhang
    • 1
  • Buwei Yu
    • 1
  1. 1.Department of Anesthesiology, Ruijin Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiPeople’s Republic of China
  2. 2.Department of AnesthesiologyPLA 455th HospitalShanghaiPeople’s Republic of China

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