Oxidized ATP (oATP) attenuates proinflammatory signaling via P2 receptor-independent mechanisms
Oxidized ATP (oATP) attenuates proinflammatory signaling via P2 receptor-independent mechanisms
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DOI：
10.1038/sj.bjp.0705470
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发表时间：
2003-10-01
影响因子：
7.3
通讯作者：
Dubyak, GR
中科院分区：
文献类型：
--
作者：
Beigi, RD;Kertesy, SB;Dubyak, GR
1高碘酸氧化ATP（oATP），共价修饰核苷酸结合蛋白，可以显着减弱促炎信号。尽管oATP可不可逆地拮抗P2 X（7）核苷酸受体（P2 X（7）R），但oATP的抗炎作用是否主要通过其对P2 X（7）R的作用介导尚不清楚。在这里，我们描述了oATP对缺乏P2 X（7）R表达的三种人类细胞类型中促炎反应的抑制作用：人脐静脉内皮细胞（HUVEC）、HEK 293细胞和1321 N1星形胶质细胞。2 oATP使肿瘤坏死因子-α刺激的白细胞介素（IL）-8分泌减少40- 70在HUVEC和1321 N1细胞中通过IL-1 β，以及在HUVEC中通过内毒素，在所有三种细胞类型中通过TNF-α。在野生型HEK细胞或稳定表达重组P2 X（7）R的HEK细胞中，oATP对TNF-α刺激的IL-8分泌的减弱作用相似。3 oATP还减弱了在HEK或1321 N1细胞中表达的核因子-κ B-荧光素酶报告基因的表达，但不影响IkappaB的快速下调。4 oATP对尿苷三磷酸诱导的HEK细胞中天然P2 Y（2）受体的激活没有影响，但降低了ADP作为天然P2 Y（1）受体激动剂的效力和功效。然而，用特异性拮抗剂MRS 2216抑制P2 Y（1）受体并不能模拟oATP对TNF-α刺激的IL-8分泌的影响。5尽管1321 N1星形胶质细胞缺乏任何已知的P2受体亚型的表达，但oATP显著抑制这些细胞中的胞外ATP酶活性，导致胞外ATP的显著积累。6总之，oATP可通过独立于已知P2受体亚型的表达或激活的机制减弱促炎信号传导。
1 Periodate-oxidized ATP (oATP), which covalently modifies nucleotide-binding proteins, can significantly attenuate proinflammatory signaling. Although the P2X(7) nucleotide receptor (P2X(7)R) is irreversibly antagonized by oATP, it is unclear whether anti-inflammatory actions of oATP are predominantly mediated via its actions on P2X(7)R. Here, we describe inhibitory effects of oATP on proinflammatory responses in three human cell types that lack expression of P2X(7)R: human umbilical vein endothelial cells (HUVEC), HEK293 cells, and 1321N1 astrocytes.2 oATP decreased by 40-70% the secretion of interleukin (IL)-8 stimulated by tumor necrosis factor-alpha (TNF-alpha) in all three cell types, by IL-1beta in HUVEC and 1321N1 cells, and by endotoxin in HUVEC. Attenuation of TNF-alpha-stimulated IL-8 secretion by oATP was similar in wild-type HEK cells or HEK cells stably expressing recombinant P2X(7)R.3 oATP also attenuated cytokine-stimulated expression of nuclear factor-kappaB-luciferase reporter genes expressed in HEK or 1321N1 cells, but did not affect the rapid downregulation of IkappaB.4 oATP had no effect on uridine triphosphate-induced activation of native P2Y(2) receptors in HEK cells, but reduced the potency and efficacy of ADP as an agonist of native P2Y(1) receptors. However, inhibition of P2Y(1) receptors with the specific antagonist MRS2216 did not mimic the effects of oATP on TNF-alpha-stimulated IL-8 secretion.5 Although 1321N1 astrocytes lack expression of any known P2 receptor subtypes, oATP markedly inhibited ecto-ATPase activity in these cells, resulting in a significant accumulation of extracellular ATP.6 In summary, oATP can attenuate proinflammatory signaling by mechanisms independent of the expression or activation of known P2 receptor subtypes.