Park Woong-Ryeon, Nakahira Masakiyo, Sugimoto Naotoshi, Bian Yang, Yashiro-Ohtani Yumi, Zhou Xu-Yu, Yang Yi-Fu, Hamaoka Toshiyuki, Fujiwara Hiromi
Department of Oncology (C6), Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Int Immunol. 2004 Feb;16(2):295-302. doi: 10.1093/intimm/dxh034.
IL-12 promotes T(h)1 development/IFN-gamma expression by activating STAT4. However, it is still unclear how STAT4 elicits IFN-gamma promoter activation. Here, we investigated the mechanism by which IL-12-activated STAT4 functions for IFN-gamma induction in TCR-triggered T cells. TCR stimulation induced high levels of IFN-gamma production depending on co-stimulation with IL-12. IL-12 stimulation greatly enhanced the promoter-binding activity of c-Jun/AP-1, a critical transcription factor for IFN-gamma gene expression in wild-type T cells, but not in STAT4-deficient (STAT4(-/-)) T cells. Comparable amounts of c-Jun were induced by TCR stimulation in both wild-type and STAT4(-/-) T cells irrespective of IL-12 co-stimulation. However, c-Jun bound to STAT4 in IL-12-co-stimulated wild-type T cells. c-Jun forming a complex with STAT4 efficiently interacted with the AP-1-related sequence of the IFN-gamma promoter. Such an enhanced c-Jun binding did not occur in STAT4(-/-) T cells. These results show that STAT4 contributes to enhancing IFN-gamma expression by up-regulating the binding of TCR signal-induced AP-1 to the relevant promoter sequence.
白细胞介素-12通过激活信号转导和转录激活因子4（STAT4）促进辅助性T细胞1（Th1）的发育/γ干扰素（IFN-γ）表达。然而，STAT4如何引发IFN-γ启动子激活仍不清楚。在此，我们研究了白细胞介素-12激活的STAT4在T细胞受体（TCR）触发的T细胞中诱导IFN-γ的作用机制。TCR刺激依赖于与白细胞介素-12的共刺激诱导高水平的IFN-γ产生。白细胞介素-12刺激极大地增强了c-Jun/激活蛋白-1（AP-1）的启动子结合活性，c-Jun/AP-1是野生型T细胞中IFN-γ基因表达的关键转录因子，但在STAT4缺陷（STAT4(-/-)）的T细胞中则不然。无论是否有白细胞介素-12共刺激，TCR刺激在野生型和STAT4(-/-) T细胞中均诱导产生相当数量的c-Jun。然而，在白细胞介素-12共刺激的野生型T细胞中，c-Jun与STAT4结合。与STAT4形成复合物的c-Jun有效地与IFN-γ启动子的AP-1相关序列相互作用。在STAT4(-/-) T细胞中未出现这种增强的c-Jun结合。这些结果表明，STAT4通过上调TCR信号诱导的AP-1与相关启动子序列的结合，有助于增强IFN-γ表达。
