Elevation of intracellular cAMP inhibits RhoA activation and integrin-dependent leukocyte adhesion induced by chemoattractants
Elevation of intracellular cAMP inhibits RhoA activation and integrin-dependent leukocyte adhesion induced by chemoattractants
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DOI：
10.1074/jbc.272.39.24141
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发表时间：
1997-09-26
影响因子：
4.8
通讯作者：
Butcher, EC
中科院分区：
文献类型：
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作者：
Laudanna, C;Campbell, JJ;Butcher, EC
蛇形、异源三聚体G α（i）蛋白连接家族的化学引诱剂受体可以激活白细胞整联蛋白，并在免疫和炎症反应中调节白细胞运输和细胞-细胞相互作用。使用小鼠淋巴细胞系转染人甲酰肽或白细胞介素-8受体和正常的人中性粒细胞作为模型，我们表明，cAMP的功能作为门控元件的趋化因子诱导的rho依赖性信号通路，导致白细胞整合素激活和粘附。cAMP通过蛋白激酶A起作用，抑制趋化因子触发的整合素依赖性白细胞粘附。cAMP还阻止RhoA上的鸟嘌呤核苷酸交换，RhoA是rho亚家族的小GTP结合蛋白，其在几秒钟内被化学引诱物激活。相反，趋化因子触发的细胞内钙离子升高不受cAMP的影响，cAMP对rho依赖性粘附和RhoA鸟嘌呤核苷酸交换没有影响，通过独立的蛋白激酶C途径触发。这些数据表明，cAMP诱导的rho激活的抑制可能是负责cAMP的抗粘附作用，并可能有助于cAMP升高激动剂和药物的抗炎活性，此外，研究结果扩展了环核苷酸门控的概念，作为一个广泛的重要机制，在细胞内信号通路的调节和细胞活动，他们控制。
Chemoattractant receptors of the serpentine, heterotrimeric G alpha(i) protein-linked family can activate leukocyte integrins and in this role regulate leukocyte traffic and cell-cell interactions in immune and inflammatory responses. Using a mouse lymphoid cell line transfected with human formyl peptide or interleukin-8 receptors and normal human neutrophils as models, we show that cAMP functions as a gating element on the chemoattractant-induced rho-dependent signaling pathway leading to leukocyte integrin activation and adhesion. cAMP, acting through protein kinase A, inhibits chemoattractant-triggered integrin-dependent leukocyte adhesion. cAMP also prevents guanine nucleotide exchange on RhoA, a small GTP-binding protein of the rho subfamily, which is activated in seconds by chemoattractants. In contrast, chemoattractant-triggered intracellular calcium elevation is unaffected by cAMP, and cAMP has no effect on rho-dependent adhesion and RhoA guanine nucleotide exchange triggered through the independent protein kinase C pathway. These data suggest that cAMP-induced inhibition of rho activation may be responsible for the anti-adhesive effect of cAMP and may contribute to the anti-inflammatory activity of cAMP elevating agonists and drugs, Moreover, the findings extend the concept of cyclic nucleotide gating as a broadly important mechanism in the regulation of intracellular signaling pathways and the cellular activities they control.