Adenosine receptors control HIV-1 Tat-induced inflammatory responses through protein phosphatase
Adenosine receptors control HIV-1 Tat-induced inflammatory responses through protein phosphatase
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DOI：
10.1016/j.virol.2004.07.007
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发表时间：
2004-10-01
期刊：
影响因子：
3.7
通讯作者：
Geiger, JD
中科院分区：
文献类型：
--
作者：
Fotheringham, J;Mayne, M;Geiger, JD
最近，腺苷被认为是一种“代谢”开关，可以感知和指导免疫和炎症反应。炎症和促炎细胞因子的产生在HIV-1相关痴呆的发展中是重要的，HIV-1感染CNS的破坏性后果。HIV-1蛋白达特诱导CNS中的细胞死亡，并部分通过诱导内质网释放钙来激活局部炎症反应。由于腺苷受体的激活在体外和体内的几个实验范例中减少促炎细胞因子TNF-α的产生，我们假设腺苷受体激活将控制由达特诱导的细胞内钙和TNF-α产生的增加。用达特处理原代单核细胞显著增加了从IP 3库释放的细胞内钙的水平。用CGS 21680激活腺苷受体可抑制Tat诱导的细胞内钙增加90 +/- 8%，并且依赖于蛋白磷酸酶活性，因为冈田酸阻断了CGS 21680的作用。Tat诱导的TNF-α产生被CGS 21680抑制90 +/- 6%，同时用冈田酸处理阻断了CGS 21680的抑制作用。使用模型单核细胞系，CGS 21680处理增加胞质丝氨酸/苏氨酸磷酸酶。总之，这些数据表明A（2A）受体活化增加蛋白磷酸酶活性，其阻断IP 3受体调节的钙释放，并且细胞内钙的减少抑制单核细胞中TNF-α的产生。(C)2004年爱思唯尔公司All rights reserved.
Recently, adenosine has been proposed to be a "metabolic" switch that may sense and direct immune and inflammatory responses. Inflammation and pro-inflammatory cytokine production are important in development of HIV-1 associated dementia, a devastating consequence of HIV-1 infection of the CNS. The HIV-1 protein Tat induces cell death in the CNS and activates local inflammatory responses partially by inducing calcium release from the endoplasmic reticulum. Because activation of adenosine receptors decreases production of the pro-inflammatory cytokine TNF-alpha in several experimental paradigms both in vitro and in vivo, we hypothesized that adenosine receptor activation would control both increased intracellular calcium and TNF-alpha production induced by Tat. Treatment of primary monocytes with Tat significantly increased the levels of intracellular calcium released from IP3 stores. Activation of adenosine receptors with CGS 21680 inhibited Tat-induced increases of intracellular calcium by 90 +/- 8% and was dependent on protein phosphatase activity because okadaic acid blocked the actions of CGS 21680. Tat-induced TNF-alpha production was inhibited 90 +/- 6% by CGS 21680 and concurrent treatment with okadaic acid blocked the inhibitory actions of CGS 21680. Using a model monocytic cell line, CGS 21680 treatment increased cytosolic serine/threonine phosphatase. Together, these data indicate that A(2A) receptor activation increases protein phosphatase activity, which blocks IP3 receptor-regulated calcium release and reduction of intracellular calcium inhibits TNF-alpha production in monocytes. (C) 2004 Elsevier Inc. All rights reserved.