Jung S, Donhauser T, Toyka K V, Hartung H P
Department of Neurology, Julius-Maximilians Universität Würzburg, Germany.
J Autoimmun. 1997 Dec;10(6):519-29. doi: 10.1006/jaut.1997.0159.
Intracellular cAMP levels can be elevated by activation of cAMP-generating adenylate cyclase (AC) or inhibition of cAMP-cleavage by phosphodiesterases. Elevation of intracellular cAMP levels in immune cells inhibits production of some Th1-cytokines, particularly TNF-alpha, and results mainly in downregulation of the immune response. Experimental autoimmune encephalomyelitis (EAE) of Lewis rats is a disease mediated by type 1 T helper lymphocytes and macrophages and serves as a model of multiple sclerosis. In EAE we therefore tested the immunomodulatory potency of an AC-activating, stable prostacyclin analogue, iloprost, and of a potent and non-selective inhibitor of phosphodiesterases, propentofylline, which also has neuroprotective properties. Preventive treatment of Lewis rats with propentofylline (2 x 10 or 12.5 mg/ kg/d), iloprost (2 x 10 or 12.5 micrograms/kg/d), or both did not significantly ameliorate clinical or histological signs of EAE actively induced by immunization with myelin basic protein (MBP) in complete Freund's adjuvant. Furthermore, adoptive transfer EAE (AT-EAE), passively induced by injection of encephalitogenic MBP-specific Th1 lymphocytes, was not altered in its course by the combined application of iloprost (2 x 10 micrograms/kg/d) and propentofylline (2 x 20 mg/kg/d) starting on the day of cell transfer. In vitro assays demonstrated that iloprost strongly and propentofylline moderately inhibited the production of TNF-alpha by macrophages and that iloprost in vivo similarly suppressed TNF-alpha secretion, although this effect was limited to a few hours after a single injection. In contrast to macrophages, TNF-alpha production by antigen-activated encephalitogenic T helper line cells in vitro was completely resistant to modulation by these agents. In addition, the presence of iloprost, propentofylline, or both drugs during activation of the line cells in vitro did not impair their encephalitogenicity in vivo. The findings delineate immunomodulatory effects of both substances, particularly of iloprost, but fail to support a possible therapeutic role of these agents in autoimmune inflammation of the central nervous system.
细胞内cAMP水平可通过激活生成cAMP的腺苷酸环化酶（AC）或抑制磷酸二酯酶对cAMP的裂解来升高。免疫细胞内cAMP水平的升高会抑制某些Th1细胞因子的产生，尤其是肿瘤坏死因子-α（TNF-α），并主要导致免疫反应的下调。Lewis大鼠的实验性自身免疫性脑脊髓炎（EAE）是一种由1型辅助性T淋巴细胞和巨噬细胞介导的疾病，可作为多发性硬化症的模型。因此，在EAE中，我们测试了一种激活AC的稳定前列环素类似物伊洛前列素以及一种强效且非选择性的磷酸二酯酶抑制剂丙戊茶碱的免疫调节效力，丙戊茶碱也具有神经保护特性。用丙戊茶碱（2×10或12.5毫克/千克/天）、伊洛前列素（2×10或12.5微克/千克/天）或两者对Lewis大鼠进行预防性治疗，并未显著改善用完全弗氏佐剂中的髓鞘碱性蛋白（MBP）免疫主动诱导的EAE的临床或组织学症状。此外，在细胞转移当天开始联合应用伊洛前列素（2×10微克/千克/天）和丙戊茶碱（2×20毫克/千克/天），并未改变由注射致脑炎性MBP特异性Th1淋巴细胞被动诱导的过继性转移EAE（AT-EAE）的病程。体外试验表明，伊洛前列素强烈抑制、丙戊茶碱中度抑制巨噬细胞产生TNF-α，并且伊洛前列素在体内同样抑制TNF-α分泌，尽管这种作用仅限于单次注射后的几个小时。与巨噬细胞不同，体外抗原激活的致脑炎性辅助性T细胞系细胞产生TNF-α对这些药物的调节完全有抗性。此外，在体外激活系细胞期间存在伊洛前列素、丙戊茶碱或两种药物，并不损害它们在体内的致脑炎性。这些发现描述了这两种物质的免疫调节作用，特别是伊洛前列素，但不支持这些药物在中枢神经系统自身免疫性炎症中可能的治疗作用。
