Smyth M J, Ortaldo J R, Bere W, Yagita H, Okumura K, Young H A
Laboratory of Experimental Immunology, National Cancer Institute-Frederick Cancer Research and Development Center, MD 21701.
J Immunol. 1990 Aug 15;145(4):1159-66.
Our previous studies have demonstrated that high dose IL-2 (1000 U/ml) alone can induce human peripheral blood T cell pore-forming protein (PFP) mRNA expression and cytotoxic potential. We now report that the levels of IL-2 needed to induce these effects in T cells can be significantly reduced in the presence of IL-6. IL-6 and suboptimal doses of IL-2 (10 U/ml) were found to costimulate PFP mRNA expression and cytotoxic potential in resting human peripheral blood T cells, whereas IL-6 or low dose IL-2 alone had no effect. The induction of T cell PFP mRNA by IL-2/IL-6 was extremely rapid and increases in both PFP mRNA expression and cytotoxic potential were IL-6 dose dependent. The costimulatory effect of IL-6 did not appear to involve the IL-2/IL-2R pathway in as much as IL-6 did not induce IL-2 production or detectably increase IL-2R surface expression in T cells. These findings, in addition to the rapid induction of PFP mRNA by IL-2/IL-6, suggested that IL-6 can directly and independently provide an additional signal to augment the differentiation of CTL. In contrast to the results observed in T cells, IL-6 and IL-2 could enhance CD3- large granular lymphocyte (LGL) NK activity, but IL-6 either alone or in combination with IL-2 had no effect on constitutive PFP mRNA expression in resting LGL. These data further confirm that different mechanisms may be responsible for lymphokine activation of CTL and LGL in human peripheral blood. In particular it appears that IL-6 acts as a costimulatory signal with IL-2 in generating CTL and that IL-6 functions in part by acting in synergy with IL-2 to induce PFP, a major lytic protein involved in lymphocyte cytotoxicity.
我们先前的研究表明，单独使用高剂量白细胞介素-2（1000 U/ml）可诱导人外周血T细胞穿孔素（PFP）mRNA表达及细胞毒性潜能。我们现在报告，在白细胞介素-6存在的情况下，诱导T细胞产生这些效应所需的白细胞介素-2水平可显著降低。研究发现，白细胞介素-6与次优剂量的白细胞介素-2（10 U/ml）共同刺激静息人外周血T细胞中PFP mRNA表达及细胞毒性潜能，而单独的白细胞介素-6或低剂量白细胞介素-2则无此作用。白细胞介素-2/白细胞介素-6诱导T细胞PFP mRNA极其迅速，且PFP mRNA表达及细胞毒性潜能的增加均呈白细胞介素-6剂量依赖性。白细胞介素-6的共刺激作用似乎不涉及白细胞介素-2/白细胞介素-2受体途径，因为白细胞介素-6不会诱导T细胞产生白细胞介素-2，也不会使T细胞表面白细胞介素-2受体表达明显增加。这些发现，除了白细胞介素-2/白细胞介素-6对PFP mRNA的快速诱导作用外，提示白细胞介素-6可直接且独立地提供额外信号，以增强细胞毒性T淋巴细胞（CTL）的分化。与在T细胞中观察到的结果相反，白细胞介素-6和白细胞介素-2可增强CD3大颗粒淋巴细胞（LGL）的自然杀伤（NK）活性，但白细胞介素-6单独或与白细胞介素-2联合使用对静息LGL中组成性PFP mRNA表达均无影响。这些数据进一步证实，人类外周血中细胞毒性T淋巴细胞和大颗粒淋巴细胞的淋巴因子激活可能由不同机制介导。特别是，白细胞介素-6似乎在产生细胞毒性T淋巴细胞过程中与白细胞介素-2起协同刺激信号作用，且白细胞介素-6部分通过与白细胞介素-2协同作用诱导PFP发挥功能，PFP是参与淋巴细胞细胞毒性的主要溶解蛋白。
