Regulation of MHC class II expression in glioma cells by class II transactivator (CIITA)
Regulation of MHC class II expression in glioma cells by class II transactivator (CIITA)
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作者：
Takamura, Y;Ikeda, H;Sato, N
我们首先将12个恶性胶质瘤细胞系分为三个不同的组（类型1-3）相对于主要组织相容性复合体（MHC）II类表达和分析每组的基础上的不同表达状态的II类反式激活因子（CIITA）基因。1型胶质瘤（2/12）显示所有II类分子的组成型表达，其可能通过激活B细胞特异性CIITA启动子III介导。2型胶质瘤代表恶性胶质瘤细胞系的主要表型（66.7%），并且在该表型中，干扰素-γ（IFN-γ）诱导MHC II类表达。胶质瘤组织样本的分析显示，CIITA启动子IV中检测到9 11例（81.8%），然而，启动子III中只有两个（18.2%）。此外，从新鲜肿瘤样品中获得的培养的神经胶质瘤细胞在IFN-γ存在下上调CIITA和II类分子的表达，强烈表明2型神经胶质瘤可能在神经胶质瘤组织中占主导地位。胶质瘤3型（12例中的2例）显示CIITA转录本，但即使在IFN-γ存在下也丧失了MHC II类表达。此外，我们确定，组成型MHC II类表达的胶质瘤细胞系（1型）的CIITA基因的转录激活的结果。这一现象是由CIITA启动子III转录起始位点上游6 kb以上的组蛋白乙酰化介导的。此外，将CIITA启动子IV和启动子III稳定转染到MHC II类诱导型细胞系中，恢复了所有II类分子的组成型表达。这些研究为了解II类分子在胶质瘤中表达的分子基础奠定了基础。(C)2003 Wiley-Liss，Inc.
We first classified 12 malignant glioma cell lines into three different groups (types 1-3) with respect to major histocompatibility complex (MHC) class II expression and analyzed each group based on the different expression status of the class II transactivator (CIITA) gene. Glioma type 1 (2 of 12) showed constitutive expression of all class II molecules that might be mediated by activation of B cell-specific CIITA promoter III. Glioma type 2 represented the major phenotype (66.7 %) of malignant glioma cell lines, and MHC class II expression was induced by interferon-gamma (IFN-gamma) in this phenotype. Analysis of glioma tissue samples revealed that CIITA promoter IV was detected in 9 of 11 patients (81.8%); however, promoter III was only in two (18.2%). Moreover, cultured glioma cells obtained from a fresh tumor sample upregulated expression of CIITA and class II molecules in the presence of IFN-gamma, strongly suggesting that glioma type 2 might be predominant in glioma tissues. Glioma type 3 (2 of 12) showed CIITA transcripts but loss of MHC class II expression even in the presence of IFN-gamma. In addition, we determined that the constitutive MHC class II expression in the glioma cell lines (type 1) was the result of transcriptional activation of the CIITA gene. This phenomenon was mediated by global histone acetylation over 6 kb upstream from the transcriptional start site of CIITA promoter III. Moreover, stable transfection of CIITA promoter IV as well as promoter III into MHC class Il inducible cell lines restored the constitutive expression of all class II molecules. These studies lay the foundation to understand the molecular basis for the expression of class Il molecules in gliomas. (C) 2003 Wiley-Liss, Inc.