Walker W, Aste-Amezaga M, Kastelein R A, Trinchieri G, Hunter C A
Department of Pathobiology, University of Pennsylvania, and The Wistar Institute, Philadelphia, PA 19104, USA.
J Immunol. 1999 May 15;162(10):5894-901.
NK cells play an important role in innate immune resistance, particularly through synthesis of the pro-inflammatory cytokine IFN-gamma. This study compares the abilities of the cytokine IL-18 and the costimulatory cell surface molecule CD28 to enhance IL-12-driven IFN-gamma production by NK cells. Studies with other cytokines (IL-1beta, IL-6, TNF-alpha, IL-15) showed that IL-18 or anti-CD28 treatments were the most efficient inducers of IFN-gamma when combined with IL-12. The ability of IL-18 to enhance IFN-gamma was shown to be dependent on the presence of IL-12. Similarly, although anti-CD28 stimulation alone could enhance IFN-gamma synthesis, this effect was significantly increased in the presence of IL-12. Although neither method of costimulation required de novo protein synthesis for their effects on IFN-gamma mRNA expression, these molecules used distinct mechanisms. Specifically, nuclear run-on analysis revealed that IL-18 in combination with IL-12 enhanced the rate of transcription of the IFN-gamma gene. Conversely, treatment with anti-CD28 plus IL-12 did not significantly up-regulate the rate of transcription of the IFN-gamma gene, but stabilized IFN-gamma mRNA expression within NK cells. These findings illustrate costimulatory pathways that result in potent IFN-gamma responses by NK cells and show that although IL-18 and anti-CD28 can enhance the synthesis of IL-12-driven IFN-gamma, they employ molecular mechanisms that are distinct from one another.
自然杀伤细胞在先天性免疫抵抗中发挥重要作用，特别是通过合成促炎细胞因子γ干扰素。本研究比较了细胞因子白细胞介素-18和共刺激细胞表面分子CD28增强白细胞介素-12驱动的自然杀伤细胞产生γ干扰素的能力。对其他细胞因子（白细胞介素-1β、白细胞介素-6、肿瘤坏死因子-α、白细胞介素-15）的研究表明，白细胞介素-18或抗CD28处理与白细胞介素-12联合使用时，是γ干扰素最有效的诱导剂。白细胞介素-18增强γ干扰素的能力被证明依赖于白细胞介素-12的存在。同样，虽然单独的抗CD28刺激可以增强γ干扰素的合成，但在白细胞介素-12存在的情况下，这种效果会显著增加。尽管两种共刺激方法对γ干扰素mRNA表达的影响都不需要从头合成蛋白质，但这些分子使用了不同的机制。具体而言，细胞核连续分析显示，白细胞介素-18与白细胞介素-12联合使用可提高γ干扰素基因的转录速率。相反，抗CD28加白细胞介素-12处理并没有显著上调γ干扰素基因的转录速率，但稳定了自然杀伤细胞内γ干扰素mRNA的表达。这些发现阐明了导致自然杀伤细胞产生有效γ干扰素反应的共刺激途径，并表明虽然白细胞介素-18和抗CD28可以增强白细胞介素-12驱动的γ干扰素合成，但它们采用的分子机制彼此不同。
