Hyodo Y, Matsui K, Hayashi N, Tsutsui H, Kashiwamura S, Yamauchi H, Hiroishi K, Takeda K, Tagawa Y, Iwakura Y, Kayagaki N, Kurimoto M, Okamura H, Hada T, Yagita H, Akira S, Nakanishi K, Higashino K
Third Department of Internal Medicine, Laboratory of Host Defenses Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
J Immunol. 1999 Feb 1;162(3):1662-8.
IL-18 is a powerful inducer of IFN-gamma production, particularly in collaboration with IL-12. IL-18, like IL-12, also augments NK activity. Here we investigated the molecular mechanism underlying the up-regulation of killing activity of NK cells by IL-18. IL-18, like IL-12, dose dependently enhanced NK activity of splenocytes. This action was further enhanced by costimulation with IL-12. Treatment with anti-IL-2R Ab did not affect IL-18- and/or IL-12-augmented NK activity, and splenocytes from IFN-gamma-deficient mice showed enhanced NK activity following stimulation with IL-12 and/or IL-18. Splenocytes from the mice deficient in both IL-12 and IL-18 normally responded to IL-18 and/or IL-12 with facilitated NK activity, suggesting that functional NK cells develop in the absence of IL-12 and IL-18. IL-18R, as well as IL-12R mRNA, was constitutively expressed in splenocytes from SCID mice, which lack T cells and B cells but have intact NK cells, and in those from IL-12 and IL-18 double knockout mice. NK cells isolated from SCID splenocytes expressed IL-18R on their surface. IL-18, in contrast to IL-12, did not enhance mRNA expression of perforin, a key molecule for exocytosis-mediated cytotoxicity. However, pretreatment with concanamycin A completely inhibited this IL-18- and/or IL-12-augmented NK activity. Furthermore, IL-18, like IL-12, failed to enhance NK activity of splenocytes from perforin-deficient mice. These data suggested that NK cells develop and express IL-12R and IL-18R in the absence of IL-12 or IL-18, and that both IL-18 and IL-12 directly and independently augment perforin-mediated cytotoxic activity of NK cells.
白细胞介素-18（IL-18）是γ干扰素（IFN-γ）产生的强力诱导剂，尤其是在与白细胞介素-12（IL-12）协同作用时。与IL-12一样，IL-18也能增强自然杀伤细胞（NK）的活性。在此，我们研究了IL-18上调NK细胞杀伤活性的分子机制。与IL-12一样，IL-18剂量依赖性地增强脾细胞的NK活性。IL-12的共刺激进一步增强了这一作用。用抗IL-2受体抗体处理并不影响IL-18和/或IL-12增强的NK活性，且来自IFN-γ缺陷小鼠的脾细胞在受到IL-12和/或IL-18刺激后显示出增强的NK活性。来自IL-12和IL-18双缺陷小鼠的脾细胞通常对IL-18和/或IL-12有反应，NK活性增强，这表明功能性NK细胞在没有IL-12和IL-18的情况下也能发育。IL-18受体（IL-18R）以及IL-12受体（IL-12R）mRNA在严重联合免疫缺陷（SCID）小鼠的脾细胞中组成性表达，这些小鼠缺乏T细胞和B细胞，但NK细胞完整，在来自IL-12和IL-18双敲除小鼠的脾细胞中也是如此。从SCID脾细胞中分离出的NK细胞在其表面表达IL-18R。与IL-12不同，IL-18并未增强穿孔素（一种胞吐介导的细胞毒性关键分子）的mRNA表达。然而，用 concanamycin A预处理完全抑制了这种IL-18和/或IL-12增强的NK活性。此外，与IL-12一样，IL-18未能增强来自穿孔素缺陷小鼠的脾细胞的NK活性。这些数据表明，NK细胞在没有IL-12或IL-18的情况下发育并表达IL-12R和IL-18R，且IL-18和IL-12都直接且独立地增强NK细胞穿孔素介导的细胞毒性活性。
