Li-Weber M, Krafft H, Krammer P H
Tumor Immunology Program, German Cancer Research Center Heidelberg.
J Immunol. 1993 Aug 1;151(3):1371-82.
IL-4 is a pleiotropic cytokine that regulates T cell-dependent immune responses. We identified and characterized a novel enhancer, positive regulatory element I (PRE-I), in the 5' region of the promoter of the human IL-4 gene. The functional core element of PRE-I is -239GTGTAATTTCCTATGC-224. Two novel nuclear proteins, POS-1 and POS-2, were found to specifically bind to the core element and function as transcriptional activators. The function of PRE-I did not require T cell stimulation and was not restricted to T cells. However, mutations in the core element of PRE-I significantly reduced the promoter activity and completely impaired inducibility of the promoter. In the human IL-4 promoter the enhancer function of PRE-I is strongly suppressed. A negative regulatory element (NRE), 45 bp upstream of PRE-I, directly represses PRE-I enhancer activity. Repression of PRE-I by NRE does not require a particular order or arrangement of positive and negative regulatory sequences. The IL-4 NRE may also down-regulate other enhancers, such as the murine sarcoma virus and the SV40 enhancers. Thus, the IL-4 NRE may represent a new type of cis regulatory element that carries the properties of a silencer but down-regulates enhancer instead of basal promoter activity.
白细胞介素-4是一种多效性细胞因子，可调节T细胞依赖性免疫反应。我们在人白细胞介素-4基因启动子的5'区域鉴定并表征了一种新型增强子，即正向调节元件I（PRE-I）。PRE-I的功能核心元件为-239GTGTAATTTCCTATGC-224。发现两种新型核蛋白POS-1和POS-2能特异性结合核心元件并作为转录激活因子发挥作用。PRE-I的功能不需要T细胞刺激，且不限于T细胞。然而，PRE-I核心元件中的突变显著降低了启动子活性，并完全损害了启动子的诱导性。在人白细胞介素-4启动子中，PRE-I的增强子功能受到强烈抑制。PRE-I上游45 bp处的负向调节元件（NRE）直接抑制PRE-I增强子活性。NRE对PRE-I的抑制不需要正负调节序列的特定顺序或排列。白细胞介素-4 NRE也可能下调其他增强子，如鼠肉瘤病毒和SV40增强子。因此，白细胞介素-4 NRE可能代表一种新型的顺式调节元件，它具有沉默子的特性，但下调增强子而非基础启动子活性。
