Cyclic AMP modulates the functional plasticity of immature dendritic cells by inhibiting Src-like kinases through protein kinase A-mediated signaling
Cyclic AMP modulates the functional plasticity of immature dendritic cells by inhibiting Src-like kinases through protein kinase A-mediated signaling
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DOI：
10.1074/jbc.m403355200
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发表时间：
2004-07-30
影响因子：
4.8
通讯作者：
Racioppi, L
中科院分区：
文献类型：
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作者：
Galgani, M;De Rosa, V;Racioppi, L
未成熟的树突状细胞（iDC）可以通过增加细胞内cAMP浓度的介体来指示免疫应答朝向非炎症途径。这种现象与环核苷抑制促炎细胞因子释放而不影响树突状细胞（DC）的分化过程的能力有关。在这里，我们研究了cAMP调节内毒素信号传导的能力，通过将DCs暴露于外源性8-溴环AMP，在存在或不存在H89的情况下，H89是蛋白激酶A的选择性抑制剂，环核苷的主要分子靶点之一。cAMP影响早期脂多糖诱导的信号级联反应，使NF-κ B、p38和ERK通路的激活与c-Src和林恩激酶的刺激分离。这种现象被H89阻止了。Src样酪氨酸激酶的药理学阻断诱导了相当的结果，证实了该酶家族参与了控制人单核细胞衍生的iDC中细胞因子释放的机制。我们提出cAMP-蛋白激酶A依赖性通路通过在Src样激酶水平上门控Toll样受体信号传导来调节iDCs的功能可塑性。
Immature dendritic cells (iDCs) can be instructed to polarize the immune response toward a noninflammatory pathway by mediators that increase the intracellular concentration of cAMP. This phenomenon is associated with the ability of the cyclic nucleoside to inhibit the release of pro-inflammatory cytokines without affecting the differentiation process of the dendritic cells (DCs). Here we investigated the ability of cAMP to modulate the endotoxin signaling by exposing DCs to exogenous 8-bromium-cyclic AMP in the presence or absence of H89, a selective inhibitor of the protein kinase A, one of the major molecular targets of the cyclic nucleoside. cAMP affects the early lipopolysaccharide-induced signaling cascade dissociating the activation of NF-kappaB, p38, and ERK pathways from the stimulation of c-Src and Lyn kinases. This phenomenon was prevented by H89. The pharmacological block of Src-like tyrosine kinases induces comparable results confirming the involvement of this family of enzymes in the mechanism controlling the release of cytokines in human monocyte-derived iDCs. We propose that the cAMP-protein kinase A-dependent pathway regulates the functional plasticity of iDCs by gating the Toll-like receptor signaling at the level of Src-like kinases.