A putative osmoreceptor system that controls neutrophil function through the release of ATP, its conversion to adenosine, and activation of A2 adenosine and P2 receptors
A putative osmoreceptor system that controls neutrophil function through the release of ATP, its conversion to adenosine, and activation of A2 adenosine and P2 receptors
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DOI：
10.1189/jlb.0204066
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发表时间：
2004-07-01
影响因子：
5.5
通讯作者：
Junger, WG
中科院分区：
文献类型：
--
作者：
Chen, Y;Shukla, A;Junger, WG
我们之前已经证明，高渗应激 (HS) 可以通过环磷酸腺苷抑制趋化剂诱导的中性粒细胞反应，并通过 p38 丝裂原激活蛋白激酶 (MAPK) 激活增强这些反应。根本机制尚不清楚。在这里，我们报告说，HS剂量依赖性地从中性粒细胞中释放腺苷5'-三磷酸（ATP），并且细胞外ATP迅速转化为腺苷或激活p38 MAPK并增强N-甲酰基-甲硫氨酰-苯丙氨酸诱导的超氧化物形成。相反，腺苷抑制超氧化物的形成。腺苷脱氨酶治疗消除了 HS 的抑制作用，表明 HS 通过腺苷生成抑制中性粒细胞。中性粒细胞表达 mRNA，编码所有已知的 PI 腺苷受体（A1、A2a、A2b 和 A3）以及核苷酸受体 P2Y2、P2Y4、P2Y6、P2Y11 和 P2X7。 A2 受体激动剂模仿 HS 的抑制作用； A2 受体拮抗剂 8-(对磺基苯基)茶碱、3,7-二甲基-1-(2-丙炔基)黄嘌呤、1,3,7-三甲基-8-(3-氯苯乙烯基)黄嘌呤和 3-丙基黄嘌呤，而非 A1 和 A3 受体拮抗剂，降低了 HS 的抑制作用，表明 HS 通过 A2 受体激活来抑制中性粒细胞。 P2 受体拮抗剂抵消了 ATP 的增强作用，表明 HS 通过 P2 受体激活来共刺激中性粒细胞。我们得出结论，高渗应激通过单分子 (ATP) 及其代谢物（腺苷）调节中性粒细胞功能，分别通过激活 P2 和 A2 受体使用正反馈机制和负反馈机制。
We have previously shown that hypertonic stress (HS) can suppress chemoattractant-induced neutrophil responses via cyclic adenosine monophosphate and enhance these responses through p38 mitogen-activated protein kinase (MAPK) activation. The underlying mechanisms are unknown. Here, we report that HS dose-dependently releases adenosine 5'-triphosphate (ATP) from neutrophils and that extracellular ATP is rapidly converted to adenosine or activates p38 MAPK and enhances N-formyl-methionyl-lencyl-phenylalanine-induced superoxide formation. In contrast, adenosine suppresses superoxide formation. Adenosine deaminase treatment abolished the suppressive effect of HS, indicating that HS inhibits neutrophils through adenosine generation. Neutrophils express mRNA, encoding all known PI adenosine receptors (A1, A2a, A2b, and A3) and the nucleotide receptors P2Y2, P2Y4, P2Y6, P2Y11, and P2X7. A2 receptor agonists mimicked the suppressive effects of HS; the A2 receptor antagonists 8-(p-sulfophenyl)theophylline, 3,7-dimethyl-1-(2-propynyl)xanthine, 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine, and 3-propylxanthine, but not A1 and A3 receptor antagonists, decreased the suppressive effect of HS, indicating that HS suppresses neutrophils via A2 receptor activation. Antagonists of P2 receptors counteracted the enhancing effects of ATP, suggesting that HS costimulates neutrophils by means of P2 receptor activation. We conclude that hypertonic stress regulates neutrophil function via a single molecule (ATP) and its metabolite (adenosine), using positive- and negative-feedback mechanisms through the activation of P2 and A2 receptors, respectively.