THE ADENOSINE NEUTROPHIL PARADOX RESOLVED - HUMAN NEUTROPHILS POSSESS BOTH A1 AND A2 RECEPTORS THAT PROMOTE CHEMOTAXIS AND INHIBIT O-2- GENERATION, RESPECTIVELY
THE ADENOSINE NEUTROPHIL PARADOX RESOLVED - HUMAN NEUTROPHILS POSSESS BOTH A1 AND A2 RECEPTORS THAT PROMOTE CHEMOTAXIS AND INHIBIT O-2- GENERATION, RESPECTIVELY
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DOI：
10.1172/jci114547
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发表时间：
1990-04-01
影响因子：
15.9
通讯作者：
WILLIAMS, M
中科院分区：
文献类型：
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作者：
CRONSTEIN, BN;DAGUMA, L;WILLIAMS, M
腺苷或其类似物占据中性粒细胞上的特定受体，减少了中性粒细胞释放有毒氧代谢物的刺激，矛盾地促进了趋化性。我们现在报告的证据表明，在中性粒细胞上发现了两种不同的腺苷受体（可能是其他细胞类型的A1和A2受体）。这些腺苷受体分别调节趋化性和氧生成。n6 -环戊基腺苷（CPA）是一种选择性A1激动剂，可促进中性粒细胞对趋化剂FMLP的趋化性，甚至优于5“n -乙基羧氨基腺苷（NECA）。相反，CPA对FMLP刺激的O2生成没有抑制作用。百日咳毒素完全消除了CPA对趋化性的促进作用，但增强了NECA对O2生成的抑制作用。秋水仙碱或长春花碱对微管的破坏也会削弱NECA对趋化性的增强作用，而这些药物对NECA对O2生成的抑制作用没有明显的干扰。FMLP受体一旦与配体结合，就会转移到高亲和力状态，并与细胞骨架结合。NECA显著增加了[3H]FMLP与细胞骨架制剂的关联，因为它抑制O2-。微管的破坏并不能阻止NECA增加[3H]FMLP与细胞骨架制剂的关联。此外，CPA （A1激动剂）并没有增加[3H]FMLP与细胞骨架以及NECA （A2激动剂）的结合。这些研究表明，一类腺苷受体（A1）的占用通过一种需要完整微管和G蛋白的机制促进趋化性，而另一类受体（A2）的参与抑制O2的产生。通过A2受体的信号不依赖于微管，对百日咳毒素不敏感，并且与[3H]FMLP与细胞骨架制剂的结合有关。
Occupancy of specific receptors on neutrophils by adenosine or its analogues diminishes the stimulated release of toxic oxygen metabolites from neutrophils, paradoxically promoting chemotaxis. We now report evidence that two distinct adenosine receptors are found on neutrophils (presumably the A1 and A2 receptors of other cell types). These adenosine receptors modulate chemotaxis and O2- generation, respectively. N6-Cyclopentyladenosine (CPA), a selective A1 agonist, promoted neutrophil chemotaxis to the chemoattractant FMLP as well as or better than 5''N-ethylcarboxamidoadenosine (NECA). In contrast, CPA did not inhibit O2- generation stimulated by FMLP. Pertussis toxin completely abolished promotion of chemotaxis by CPA but enhanced inhibition by NECA of O2- generation. Disruption of microtubules by colchicine or vinblastine also abrogated the enhancement by NECA of chemotaxis whereas these agents did not markedly interfere with inhibition by NECA of O2- generation. FMLP receptors, once they have bound ligand, shift to a high affinity state and become associated with the cytoskeleton. NECA significantly increased association of [3H]FMLP with cytoskeletal preparations as it inhibited O2-. Disruption of microtubules did not prevent NECA from increasing association of [3H]FMLP with cytoskeletal preparations. Additionally, CPA (A1 agonist) did not increase binding of [3H]FMLP to the cytoskeleton as well as NECA (A2 agonist). These studies indicate that occupancy of one class of adenosine receptors (A1) promotes chemotaxis by a mechanism requiring intact microtubules and G proteins whereas engagement of a second class of receptors (A2) inhibits O2- generation. Signalling via A2 receptors is independent of microtubules, insensitive to pertussis toxin andis associated with binding of [3H]FMLP to cytoskeletal preparations.