Yang J, Murphy T L, Ouyang W, Murphy K M
Department of Pathology and Center for Immunology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110, USA.
Eur J Immunol. 1999 Feb;29(2):548-55. doi: 10.1002/(SICI)1521-4141(199902)29:02<548::AID-IMMU548>3.0.CO;2-Z.
IFN-gamma produced by CD4+ T helper 1 (Th1) cells promotes protection against intracellular pathogens. Antigen activation of Th1 cells is an important mode of IFN-gamma induction, but here we analyze a second, antigen-nonspecific pathway capable of inducing full IFN-gamma transcription. IL-12 or IL-18 alone do not induce IFN-gamma mRNA, and only modestly augment antigen-induced IFN-gamma mRNA from Th1 cells. However, IL-12 and IL-18 together fully induce IFN-gamma transcription independently of TCR-activated signals, by a mechanism that does not simply involve Stat4 and NF-kappaB activation, but requires additional protein synthesis. Cyclosporin A inhibits TCR-induced IFN-gamma production, but not IL-12/IL-18-induced IFN-gamma production, biochemically discriminating between these pathways. These results suggest that the two pathways induce IFN-gamma production through functionally segregated but spatially overlapping cis-acting elements, similar to other genes under the control of two or more promoters.
CD4 +辅助性T细胞1（Th1）产生的干扰素-γ可促进对细胞内病原体的防御。Th1细胞的抗原激活是干扰素-γ诱导的重要模式，但在此我们分析了第二种能够诱导完整干扰素-γ转录的抗原非特异性途径。单独的白细胞介素-12或白细胞介素-18不会诱导干扰素-γ信使核糖核酸，且仅适度增强Th1细胞抗原诱导的干扰素-γ信使核糖核酸。然而，白细胞介素-12和白细胞介素-18共同作用可完全独立于TCR激活信号诱导干扰素-γ转录，其机制并非简单涉及Stat4和核因子-κB激活，而是需要额外的蛋白质合成。环孢素A抑制TCR诱导的干扰素-γ产生，但不抑制白细胞介素-12/白细胞介素-18诱导的干扰素-γ产生，从生化角度区分了这些途径。这些结果表明，这两种途径通过功能上分离但空间上重叠的顺式作用元件诱导干扰素-γ产生，类似于受两个或更多启动子控制的其他基因。
