Coffey R G, Alberts V A, Weakland L L
University of South Florida, College of Medicine, Department of Pharmacology and Therapeutics, Tampa 33612.
J Leukoc Biol. 1990 Dec;48(6):557-64. doi: 10.1002/jlb.48.6.557.
Histamine stimulated large increases of cyclic adenosine monophosphate (cAMP) in freshly isolated human blood monocytes in the presence of R02-1724, a specific cAMP phosphodiesterase inhibitor. This was mediated by H2 receptors, since it was inhibited by cimetidine but not chlorpheniramine. Stimulation was attenuated in cells aged in culture 1-2 days. Indomethacin prevented the desensitization, suggesting that a cyclooxygenase product was responsible. Desensitization was heterologous, since the adenylate cyclase responses to 5'-(N-ethylcarboxamido)adenosine (A2 receptor agonist), isoproterenol (beta-adrenoceptor agonist), and prostaglandin E2 (PGE2) also declined during culture. The loss of sensitivity to histamine was restored by incubating monocytes with PGE2 in the presence of indomethacin. The results indicate that, while PGE2 inhibits monocyte functions via cAMP, its accumulation paradoxically permits cells to escape this regulation through a heterologous desensitization of the cAMP response to itself and other agonists.
在特异性环磷酸腺苷（cAMP）磷酸二酯酶抑制剂R02-1724存在的情况下，组胺可刺激新鲜分离的人血单核细胞中cAMP大幅增加。这是由H2受体介导的，因为它可被西咪替丁抑制，但不能被氯苯那敏抑制。在培养1-2天的老化细胞中，刺激作用减弱。吲哚美辛可防止脱敏，提示环氧化酶产物起作用。脱敏是异源的，因为在培养过程中，腺苷酸环化酶对5'-（N-乙基甲酰胺基）腺苷（A2受体激动剂）、异丙肾上腺素（β-肾上腺素能受体激动剂）和前列腺素E2（PGE2）的反应也会下降。在吲哚美辛存在的情况下，用PGE2孵育单核细胞可恢复对组胺的敏感性丧失。结果表明，虽然PGE2通过cAMP抑制单核细胞功能，但其积累却反常地使细胞通过对自身和其他激动剂的cAMP反应的异源脱敏而逃避这种调节。
