Barbulescu K, Becker C, Schlaak J F, Schmitt E, Meyer zum Büschenfelde K H, Neurath M F
Laboratory of Immunology, I. Medical Clinic, University of Mainz, Germany.
J Immunol. 1998 Apr 15;160(8):3642-7.
We analyzed the molecular mechanisms by which IL-12 and IL-18 induce transcriptional activity of the IFN-gamma promoter in primary human CD4+ T cells. In transfection experiments, we found that IL-18 directly induces IFN-gamma promoter activity, whereas significant activation with IL-12 required costimulation with alphaCD3/CD28. Furthermore, IL-12 caused in vivo protection of a STAT4 (-236) binding site, whereas stimulation with IL-18 or IL-12 plus alphaCD3/CD28 induced occupancy of a downstream AP-1 site. Mutation of this AP-1 site abrogated both IL-12- and IL-18-mediated promoter activation, whereas mutation of the STAT site inhibited IL-12-dependent activation. These data suggest that both AP-1 and STAT4 are required for IL-12-dependent IFN-gamma promoter activity, whereas IL-18 causes direct activation via AP-1. This differential activation of the IFN-gamma promoter gives further insights into molecular pathways governing Th1 T cell development and differentiation.
我们分析了白细胞介素-12（IL-12）和白细胞介素-18（IL-18）在原代人CD4+T细胞中诱导干扰素-γ（IFN-γ）启动子转录活性的分子机制。在转染实验中，我们发现IL-18可直接诱导IFN-γ启动子活性，而IL-12的显著激活则需要αCD3/CD28共刺激。此外，IL-12可在体内保护信号转导和转录激活因子4（STAT4）（-236）结合位点，而IL-18或IL-12加αCD3/CD28刺激可诱导下游活化蛋白-1（AP-1）位点的占据。该AP-1位点的突变消除了IL-12和IL-18介导的启动子激活，而STAT位点的突变则抑制了IL-12依赖性激活。这些数据表明，AP-1和STAT4对于IL-12依赖性IFN-γ启动子活性均是必需的，而IL-18通过AP-1导致直接激活。IFN-γ启动子的这种差异激活为调控Th1 T细胞发育和分化的分子途径提供了进一步的见解。
