Ivashkiv L B, Glimcher L H
Department of Cancer Biology, Harvard School of Public Health, Boston, Massachusetts 02115.
J Exp Med. 1991 Dec 1;174(6):1583-92. doi: 10.1084/jem.174.6.1583.
The induction of cell surface expression of class II major histocompatibility complex (MHC) antigens by interleukin (IL)-4 and interferon (IFN)-gamma is inhibited by elevation of intracellular cyclic (c)AMP, which is caused by immunomodulatory agents such as E series prostaglandins (PGEs). To investigate the mechanism of this downregulation, we have analyzed the consequences of elevating intracellular cAMP on cell surface expression, mRNA levels, and promoter activity of the murine A alpha and E beta class II MHC genes. Elevation of cAMP resulted in a coordinate repression of both basal and inducible A alpha and E beta expression. 151 and 192 base pairs of A alpha and E beta promoter sequence, respectively, were sufficient for conferring repression by cAMP on a reporter gene. A mutational analysis of the A alpha promoter revealed that cAMP downregulation is mediated by the conserved S and X1 DNA elements, which are also necessary for induction by cytokines. Downregulation by cAMP was not dependent on an intact X2 site, which is identical in sequence to the CRE element which mediates the positive regulation of several genes by cAMP. These results identify the DNA elements which mediate repression of class II MHC genes by cAMP and show that the same DNA sequences can mediate both positive and negative regulation of class II MHC expression.
白细胞介素(IL)-4和干扰素(IFN)-γ诱导的II类主要组织相容性复合体(MHC)抗原的细胞表面表达受到细胞内环(c)AMP升高的抑制,而环(c)AMP升高是由免疫调节因子如E系列前列腺素(PGEs)引起的。为了研究这种下调机制,我们分析了细胞内cAMP升高对小鼠Aα和Eβ II类MHC基因的细胞表面表达、mRNA水平和启动子活性的影响。cAMP升高导致基础型和诱导型Aα和Eβ表达的协同抑制。Aα和Eβ启动子序列的151和192个碱基对分别足以赋予cAMP对报告基因的抑制作用。对Aα启动子的突变分析表明,cAMP下调是由保守的S和X1 DNA元件介导的,这些元件也是细胞因子诱导所必需的。cAMP下调不依赖于完整的X2位点,该位点与介导几个基因由cAMP进行正调控的CRE元件序列相同。这些结果确定了介导cAMP对II类MHC基因抑制作用的DNA元件,并表明相同的DNA序列可以介导II类MHC表达的正调控和负调控。