Cutting edge: Macrophage inhibition by cyclic AMP (cAMP): Differential roles of protein kinase A and exchange protein directly activated by cAMP-1
Cutting edge: Macrophage inhibition by cyclic AMP (cAMP): Differential roles of protein kinase A and exchange protein directly activated by cAMP-1
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DOI：
10.4049/jimmunol.174.2.595
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发表时间：
2005-01-15
影响因子：
4.4
通讯作者：
Peters-Golden, M
中科院分区：
文献类型：
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作者：
Aronoff, DM;Canetti, C;Peters-Golden, M
cAMP 对巨噬细胞激活的成分具有很大的抑制作用，但参与这些作用的下游机制仍未完全确定。肺泡巨噬细胞 (AM) 中 cAMP 的升高会抑制 FcgammaR 介导的吞噬作用。我们现在报道蛋白激酶 A (PKA) 抑制剂（H-89、KT-5720 和肉豆蔻酰化 PKA 抑制肽 14-22）未能阻止大鼠 AM 中的这种抑制。我们鉴定了人类和大鼠 AM 中替代 cAMP 靶标的表达，即由 cAMP-1 (Epac-1) 直接激活的交换蛋白。使用对 PKA (N6-苯甲酰基腺苷-3',5'-cAMP) 或 Epac-1 (8-(4-氯pbeizylthio)-2'-O-methyladeizosiiie-3',5'-cAMP) 高度特异性的 cAMP 类似物，我们发现 Epac-1 的激活（而非 PKA）剂量依赖性地抑制吞噬作用。相比之下，激活PKA（而非Epac-1）抑制AM产生白三烯B-4和TNF-α，而刺激PKA或Epac-1抑制AM杀菌活性和H2O2产生。现在，这些实验鉴定了原代巨噬细胞中的 Epac-1，并定义了 Epac-1 与 PKA 在 cAMP 抑制作用中的不同作用。
cAMP has largely inhibitory effects on components of macrophage activation, yet downstream mechanisms involved in these effects remain incompletely defined. Elevation of cAMP in alveolar macrophages (AMs) suppresses FcgammaR-mediated phagocytosis. We now report that protein kinase A (PKA) inhibitors (H-89, KT-5720, and myristoylated PKA inhibitory peptide 14-22)failed to prevent this suppression in rat AMs. We identified the expression of the alternative cAMP target, exchange protein directly activated by cAMP-1 (Epac-1), in human and rat AMs. Using cAMP analogs that are highly specific for PKA (N6-benzoyladenosine-3',5'-cAMP) or Epac-1 (8-(4-chloropbeizylthio)-2'-O-methyladeizosiiie-3',5'-cAMP), we found that activation of Epac-1, but not PKA, dose-dependently suppressed phagocytosis. By contrast, activation of PKA, but not Epac-1, suppressed AM production of leukotriene B-4 and TNF-alpha, whereas stimulation of either PKA or Epac-1 inhibited AM bactericidal activity and H2O2 production. These experiments now identify Epac-1 in primary macrophages, and define differential roles of Epac- 1 vs PKA in the inbibitory effects of cAMP.