Sullivan G W, Linden J, Hewlett E L, Carper H T, Hylton J B, Mandell G L
Department of Internal Medicine, University of Virginia, Charlottesville 22908.
J Immunol. 1990 Sep 1;145(5):1537-44.
Human rTNF-alpha (greater than or equal to U/ml) decreased PMN nondirected and directed migration to FMLP to approximately 50% of control. Adenosine (100 microM) almost completely restored hrTNF-inhibited migration (nondirected from 54 to 92% and directed migration to from 54 to 93% of control). The lowest concentration of adenosine that restored hrTNF-inhibited migration was 3 microM, and the adenosine analogue, 5'-(N-cyclopropyl)-carboxamido-adenosine (CPCA) was more potent than adenosine. Although CPCA binds to A2-receptors and stimulates adenylate cyclase, the reversal of hrTNF-inhibited chemotaxis was found to be independent of both PMN cAMP content and binding to A2-receptors, because neither 8-Br-cAMP nor pertussis adenylate cyclase restored hrTNF-inhibited PMN chemotaxis and the A2-receptor antagonist, 1,3-dipropyl-7-methylxanthine decreased CPCA stimulated cAMP but enhanced CPCA-restoration of hrTNF-inhibited chemotaxis. The effect of adenosine could be augmented by inhibition of adenosine uptake and decreased by adenosine deamination. Pentoxifylline, (3,7 dimethyl-1-[5 oxo-hexyl] xanthine), like adenosine also restored PMN chemotaxis inhibited by hrTNF. The adenosine receptor antagonist, 1,3-dipropyl-8(phenyl-p-acrylate)-xanthine (BW A1433U), decreased restoration of hrTNF-inhibited chemotaxis by CPCA or pentoxifylline. Thus, the inhibitory effect of hrTNF on PMN migration can be counteracted by adenosine, CPCA, pentoxifylline, and compounds that increase adenosine availability to the surface of the PMN. Inasmuch as an A1-selective agonist N6-cyclopentyladenosine was less active, and the action of the A2-selective agonist CPCA was enhanced by an A2-receptor antagonist, we hypothesize that neither A1 or A2 receptors are involved in adenosine restoration of hrTNF-inhibited chemotaxis. Further, increased cAMP, an A2-regulated event, does not cause the effect, and adenosine restoration of hrTNF-inhibited migration does not appear to be mediated by changes in PMN [F-actin], FMLP receptor expression, or cytosolic calcium. Hence, the restoration of hrTNF-inhibited chemotaxis is controlled by a novel cyclic AMP-independent action on the PMN surface.
人重组肿瘤坏死因子-α（≥U/ml）使中性粒细胞对N-甲酰甲硫氨酰-亮氨酰-苯丙氨酸（FMLP）的非定向和定向迁移减少至对照的约50%。腺苷（100微摩尔）几乎完全恢复了hrTNF抑制的迁移（非定向迁移从对照的54%恢复到92%，定向迁移从对照的54%恢复到93%）。恢复hrTNF抑制迁移的腺苷最低浓度为3微摩尔，腺苷类似物5'-（N-环丙基）-羧酰胺腺苷（CPCA）比腺苷更有效。尽管CPCA与A2受体结合并刺激腺苷酸环化酶，但发现hrTNF抑制的趋化性逆转与中性粒细胞环磷酸腺苷（cAMP）含量和与A2受体的结合均无关，因为8-溴-cAMP和百日咳杆菌腺苷酸环化酶均未恢复hrTNF抑制的中性粒细胞趋化性，且A2受体拮抗剂1,3-二丙基-7-甲基黄嘌呤降低了CPCA刺激的cAMP，但增强了CPCA对hrTNF抑制趋化性的恢复作用。腺苷的作用可通过抑制腺苷摄取而增强，通过腺苷脱氨而减弱。己酮可可碱（3,7-二甲基-1-[5-氧代己基]黄嘌呤）与腺苷一样，也恢复了hrTNF抑制的中性粒细胞趋化性。腺苷受体拮抗剂1,3-二丙基-8-（苯基-p-丙烯酸酯）-黄嘌呤（BW A1433U）降低了CPCA或己酮可可碱对hrTNF抑制趋化性的恢复作用。因此，hrTNF对中性粒细胞迁移的抑制作用可被腺苷、CPCA、己酮可可碱以及增加中性粒细胞表面腺苷可用性的化合物所抵消。由于A1选择性激动剂N6-环戊基腺苷活性较低，且A2选择性激动剂CPCA的作用被A2受体拮抗剂增强，我们推测A1和A2受体均不参与腺苷对hrTNF抑制趋化性的恢复作用。此外，cAMP增加这一受A2调节的事件并不会产生这种效应，hrTNF抑制迁移的腺苷恢复作用似乎也不是由中性粒细胞[F-肌动蛋白]、FMLP受体表达或胞质钙的变化介导的。因此，hrTNF抑制趋化性的恢复是由对中性粒细胞表面一种新的不依赖环磷酸腺苷的作用所控制的。
