Moscovitch-Lopatin M, Petrillo R J, Pankewycz O G, Hadro E, Bleackley C R, Strom T B, Wieder K J
Department of Medicine, Beth Israel Hospital, Boston, MA 02215.
Eur J Immunol. 1991 Jun;21(6):1439-44. doi: 10.1002/eji.1830210617.
Cholera toxin irreversibly activates a 43-kDa guanosine triphosphate (GTP)-binding protein by adenosine diphosphate ribosylation, resulting in activation of adenylate cyclase and increased intracellular levels of cyclic adenosine monophosphate (cAMP). Because increases in intracellular cAMP inhibit interleukin 2 (IL 2) expression and cytotoxic T lymphocyte (CTL) generation and function in vitro and in vivo, we hypothesized that IL 2 may counteract the inhibition of CTL by cholera toxin. Activated CTL treated with IL 2 were protected from the inhibitory effects of cholera toxin. IL 2 also counteracted the inhibitory effect of cholera toxin on steady-state levels of CTL-specific serine esterase mRNA. Given the putative role of serine esterase for in vitro generated CTL effector activity, these results may account for recovery of CTL activity. Although IL 2 restored CTL function and serine esterase transcription, it did not block cholera toxin-catalyzed ribosylation of the 43-kDa GTP-binding protein, nor did it prevent the accumulation of intracellular levels of cAMP. In vivo, C57BL/6 mice challenged with the allogeneic tumor P815 had suppressed CTL function when cholera toxin was administered. These cholera toxin-treated mice died of tumor overgrowth, whereas untreated mice rejected the allogeneic tumor. Co-treatment of alloimmunized mice with cholera toxin and IL 2 prevented death from tumor overgrowth and restored CTL function; 67% of these mice survived. These data provide evidence that IL 2 acts in CTL through a mechanism independent of cholera toxin-sensitive GTP-binding protein in vitro and in vivo, despite elevated intracellular cAMP levels.
霍乱毒素通过二磷酸腺苷核糖基化作用不可逆地激活一种43 kDa的鸟苷三磷酸（GTP）结合蛋白，导致腺苷酸环化酶激活，细胞内环磷酸腺苷（cAMP）水平升高。由于细胞内cAMP水平升高在体外和体内均会抑制白细胞介素2（IL - 2）表达以及细胞毒性T淋巴细胞（CTL）的生成和功能，我们推测IL - 2可能会抵消霍乱毒素对CTL的抑制作用。用IL - 2处理激活的CTL可使其免受霍乱毒素的抑制作用。IL - 2还能抵消霍乱毒素对CTL特异性丝氨酸酯酶mRNA稳态水平的抑制作用。鉴于丝氨酸酯酶在体外产生的CTL效应活性中的假定作用，这些结果可能解释了CTL活性的恢复。尽管IL - 2恢复了CTL功能和丝氨酸酯酶转录，但它并未阻断霍乱毒素催化的43 kDa GTP结合蛋白的核糖基化，也未阻止细胞内cAMP水平的积累。在体内，用同种异体肿瘤P815攻击的C57BL / 6小鼠在给予霍乱毒素时CTL功能受到抑制。这些经霍乱毒素处理的小鼠死于肿瘤过度生长，而未处理的小鼠排斥同种异体肿瘤。用霍乱毒素和IL - 2共同处理同种免疫小鼠可防止因肿瘤过度生长而死亡并恢复CTL功能；这些小鼠中有67%存活。这些数据提供了证据，表明尽管细胞内cAMP水平升高，但IL - 2在体外和体内通过一种独立于霍乱毒素敏感的GTP结合蛋白的机制作用于CTL。
