MHC class II transactivator (CIITA) expression is upregulated in multiple myeloma cells by IFN-γ
MHC class II transactivator (CIITA) expression is upregulated in multiple myeloma cells by IFN-γ
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DOI：
10.1016/j.molimm.2007.01.009
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发表时间：
2007-04
影响因子：
3.6
通讯作者：
Mojun Zhao;Frederick L. Flynt;M. Hong;Han Chen;Carolyn A. Gilbert;Nicole T. Briley;Sophia C. E. Bolick;K. Wright;J. Piskurich
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文献类型：
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作者：
Mojun Zhao;Frederick L. Flynt;M. Hong;Han Chen;Carolyn A. Gilbert;Nicole T. Briley;Sophia C. E. Bolick;K. Wright;J. Piskurich
MHC II类反式激活因子（CIITA）在细胞核中作为MHC II类（MHC II）基因表达的主调节因子起作用。研究CIITA在多发性骨髓瘤中的调节是重要的，因为MHC表达对骨髓瘤细胞呈递抗原的能力以及免疫系统识别和破坏这种恶性肿瘤的能力至关重要。B淋巴细胞中IFN-γ对CIITA的调节通过CIITA IV型启动子（pIV）发生，该启动子是该基因的四种潜在启动子（pI-pIV）之一。为了研究多发性骨髓瘤细胞中IFN-γ对CIITA的调节，首先检查这些细胞应答IFN-γ的能力。RT-PCR分析显示，IFN-γ受体的IFN-γ结合链IFN-γR1在骨髓瘤细胞中表达，并且IRF-1表达响应于IFN-γ处理而增加。Western blotting证实STAT 1在IFN-γ作用下通过磷酸化被激活。RT-PCR和功能性启动子分析表明，IFN-γ上调CIITA pIV的活性，IRF-1或IRF-2的异位表达也是如此。体内蛋白质/DNA结合研究表明蛋白质结合在GAS、E盒和IRF-E位点。体外研究证实了IRF-1和IRF-2与CIITA pIV的结合。尽管多发性骨髓瘤细胞表达PRDI-BF 1/Blimp-1（一种抑制CIITA III型和IV型启动子的因子），但它们保留了上调CIITA pIV和MHC II表达以响应IFN-γ处理的能力。这些发现首次证明，尽管PRDI-BF 1/Blimp-1通过限制CIITA和MHC II表达而降低了这些细胞呈递抗原的组成性能力，但有可能通过使用细胞因子如IFN-γ来增强这种表达。
The MHC class II transactivator (CIITA) acts in the cell nucleus as the master regulator of MHC class II (MHC II) gene expression. It is important to study CIITA regulation in multiple myeloma since MHC expression is central to ability of myeloma cells to present antigen and to the ability of the immune system to recognize and destroy this malignancy. Regulation of CIITA by IFN-γ in B lymphocytes occurs through the CIITA type IV promoter (pIV), one of the four potential promoters (pI–pIV) of this gene. To investigate regulation of CIITA by IFN-γ in multiple myeloma cells, first the ability of these cells to respond to IFN-γ was examined. RT-PCR analyses show that IFN-γR1, the IFN-γ-binding chain of the IFN-γ receptor, is expressed in myeloma cells and IRF-1 expression increases in response to IFN-γ treatment. Western blotting demonstrates that STAT1 is activated by phosphorylation in response to IFN-γ. RT-PCR and functional promoter analyses show that IFN-γ upregulates the activity of CIITA pIV, as does ectopic expression of IRF-1 or IRF-2. In vivo protein/DNA binding studies demonstrate protein binding at the GAS, E box and IRF-E sites. In vitro studies confirm the binding of IRF-1 and IRF-2 to CIITA pIV. Although multiple myeloma cells express PRDI-BF1/Blimp-1, a factor that represses both the CIITA type III and IV promoters, they retain the capability to upregulate CIITA pIV and MHC II expression in response to IFN-γ treatment. These findings are the first to demonstrate that although PRDI-BF1/Blimp-1 diminishes the constitutive ability of these cells to present antigen by limiting CIITA and MHC II expression, it is possible to enhance this expression through the use of cytokines, like IFN-γ.