Melmon K L, Bourne H R, Weinstein Y, Shearer G M, Kram J, Bauminger S
J Clin Invest. 1974 Jan;53(1):13-21. doi: 10.1172/JCI107530.
Histamine, beta-adrenergic amines, and prostaglandins inhibited hemolytic plaque formation by splenic leukocytes from immunized mice. The same agents had previously been shown to prevent both the IgE-mediated release of histamine from human basophils and the immunologically specific cytolytic activity of murine lymphocytes, through stimulation of the production of cyclic AMP in leukocytes. We therefore tested the hypothesis that cyclic AMP might mediate an inhibitory effect of these drugs by comparing the ability of these agents to inhibit plaque formation with their effects on cyclic AMP accumulation in leukocytes. In splenic cells from three mouse strains, the dose-dependent effects of these agents of cyclic AMP correlated with their inhibition of plaque formation. Beta- but not alpha-adrenergic agonists were effective in both systems, and the effects of isoproterenol were inhibited by propranolol. Histamine was approximately equipotent with isoproterenol in both systems. Two prostaglandins (E(1) and E(2)) were effective in both systems, but prostaglandin F(2alpha) was not. Dibutyryl cyclic AMP, a lipid-soluble analog of the endogenous nucleotide, inhibited plaque formation by cells of all three strains. Theophylline, an inhibitor of cyclic AMP degradation, inhibited plaque formation slightly, but potentiated the effects of histamine, isoproterenol, and the prostaglandins on both cyclic AMP accumulation and plaque formation. Finally, cholera enterotoxin, a potent activator of adenyl cyclase, produced a delayed inhibition of plaque formation and a parallel increase in leukocyte cyclic AMP content; both effects of the toxin were blocked by canine antitoxin. These results suggest that leukocyte cyclic AMP may act as a "second messenger" to suppress plaque formation in vitro. The inhibitory effects of hormones and cyclic AMP on plaque formation are strikingly similar to their effects on in vitro models of immediate and cell-mediated hypersensitivity. The physiologic significance of these findings is not yet known.
组胺、β-肾上腺素能胺和前列腺素可抑制免疫小鼠脾脏白细胞的溶血空斑形成。此前已表明，相同的这些物质可通过刺激白细胞中环状AMP的产生，来阻止IgE介导的人嗜碱性粒细胞组胺释放以及小鼠淋巴细胞的免疫特异性溶细胞活性。因此，我们通过比较这些物质抑制空斑形成的能力与其对白细胞中环状AMP积累的影响，来检验环状AMP可能介导这些药物抑制作用的假说。在来自三种小鼠品系的脾细胞中，这些物质对环状AMP的剂量依赖性效应与其对空斑形成的抑制作用相关。β-肾上腺素能激动剂而非α-肾上腺素能激动剂在两个系统中均有效，异丙肾上腺素的作用可被普萘洛尔抑制。在两个系统中，组胺与异丙肾上腺素的效力大致相当。两种前列腺素（E(1)和E(2)）在两个系统中均有效，但前列腺素F(2α)无效。二丁酰环状AMP是内源性核苷酸的脂溶性类似物，可抑制所有三种品系细胞的空斑形成。茶碱是环状AMP降解的抑制剂，可轻微抑制空斑形成，但可增强组胺、异丙肾上腺素和前列腺素对环状AMP积累和空斑形成的作用。最后，霍乱肠毒素是腺苷酸环化酶的强效激活剂，可产生对空斑形成的延迟抑制以及白细胞环状AMP含量的平行增加；毒素的这两种作用均被犬抗毒素阻断。这些结果表明，白细胞环状AMP可能作为一种“第二信使”在体外抑制空斑形成。激素和环状AMP对空斑形成的抑制作用与其对速发型和细胞介导超敏反应体外模型的作用极为相似。这些发现的生理意义尚不清楚。
