Takamura Yukio, Ikeda Hideyuki, Kanaseki Takayuki, Toyota Minoru, Tokino Takashi, Imai Kohzoh, Houkin Kiyohiro, Sato Noriyuki
Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Glia. 2004 Mar;45(4):392-405. doi: 10.1002/glia.10343.
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 II 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 II molecules in gliomas.
我们首先根据主要组织相容性复合体（MHC）II类分子的表达情况，将12种恶性胶质瘤细胞系分为三个不同的组（1 - 3型），并基于II类反式激活因子（CIITA）基因的不同表达状态对每组进行分析。1型胶质瘤（12个中有2个）表现出所有II类分子的组成型表达，这可能是由B细胞特异性CIITA启动子III的激活介导的。2型胶质瘤代表了恶性胶质瘤细胞系的主要表型（66.7%），在该表型中，MHC II类分子的表达由γ干扰素（IFN-γ）诱导。对胶质瘤组织样本的分析显示，11名患者中有9名（81.8%）检测到CIITA启动子IV；然而，启动子III仅在2名患者中检测到（18.2%）。此外，从新鲜肿瘤样本中获得的培养胶质瘤细胞在存在IFN-γ的情况下上调了CIITA和II类分子的表达，强烈表明2型胶质瘤可能在胶质瘤组织中占主导地位。3型胶质瘤（12个中有2个）即使在存在IFN-γ的情况下也显示有CIITA转录本，但MHC II类分子表达缺失。此外，我们确定胶质瘤细胞系（1型）中组成型MHC II类分子表达是CIITA基因转录激活的结果。这种现象是由CIITA启动子III转录起始位点上游超过6 kb的整体组蛋白乙酰化介导的。此外，将CIITA启动子IV以及启动子III稳定转染到MHC II类可诱导细胞系中可恢复所有II类分子的组成型表达。这些研究为理解胶质瘤中II类分子表达的分子基础奠定了基础。
