Sisk T J, Gourley T, Roys S, Chang C H
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
J Immunol. 2000 Sep 1;165(5):2511-7. doi: 10.4049/jimmunol.165.5.2511.
The MHC class II transactivator (CIITA) activates the expression of multiple genes involved in Ag presentation, but inhibits Th2-type cytokine production, including IL-4, during Th1 cell differentiation. Th1 cells derived from CIITA-deficient mice produce both Th1- and Th2-type cytokines, and the introduction of CIITA to Th2 cells down-regulates Th2-type cytokine gene transcription. Here we show that the IL-4 promoter is regulated by multiple protein-protein interactions among CIITA, NF-AT, and coactivator CBP/p300. The introduction of CBP/p300 and NF-AT enhances the IL-4 promoter activity, and this activation was repressed by CIITA. Furthermore, our data show that CIITA competes with NF-AT to bind CBP/p300 and that this competition dramatically influences transcriptional activation of the IL-4 promoter. We identified two domains of CIITA that interact with two distinct domains of CBP/p300 that are also recognized by NF-AT. CIITA mutants that retain the ability to interact with CBP/p300 are sufficient to inhibit NF-AT-mediated IL-4 gene expression.
主要组织相容性复合体（MHC）II类反式激活因子（CIITA）可激活多个参与抗原呈递的基因的表达，但在Th1细胞分化过程中会抑制包括IL-4在内的Th2型细胞因子的产生。源自CIITA缺陷小鼠的Th1细胞会产生Th1型和Th2型细胞因子，而将CIITA导入Th2细胞会下调Th2型细胞因子基因的转录。在此，我们表明IL-4启动子受CIITA、活化T细胞核因子（NF-AT）和共激活因子CBP/p300之间多种蛋白质-蛋白质相互作用的调控。导入CBP/p300和NF-AT可增强IL-4启动子活性，而这种激活会被CIITA抑制。此外，我们的数据表明CIITA与NF-AT竞争结合CBP/p300，且这种竞争对IL-4启动子的转录激活有显著影响。我们鉴定出CIITA的两个结构域，它们与CBP/p300的两个不同结构域相互作用，而这两个结构域也能被NF-AT识别。保留与CBP/p300相互作用能力的CIITA突变体足以抑制NF-AT介导的IL-4基因表达。
