Pisapia Laura, Pozzo Giovanna Del, Barba Pasquale, Citro Alessandra, Harris Paul E, Maffei Antonella
Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, Naples, Italy.
Department of Medicine of Columbia University Medical Center, New York, NY, USA.
Results Immunol. 2012 Sep 27;2:174-83. doi: 10.1016/j.rinim.2012.09.001. eCollection 2012.
We previously demonstrated that, in ex vivo cultures, IFNα downregulates the expression of MHC class II (MHCII) genes in human non-professional APCs associated with pancreatic islets. IFNα has an opposing effect on MHCII expression in professional APCs. In this study, we found that the mechanism responsible for the IFNα-mediated MHCII's downregulation in human MHCII-positive non-professional antigen presenting human non-hematopoietic cell lines is the result of the negative feedback system that regulates cytokine signal transduction, which eventually inhibits promoters III and IV of CIITA gene. Because the CIITA-PIV isoform is mostly responsible for the constitutive expression of MHCII genes in non-professional APCs, we pursued and achieved the specific knockdown of CIITA-PIV mRNA in our in vitro system, obtaining a partial silencing of MHCII molecules similar to that obtained by IFNα. We believe that our results offer a new understanding of the potential significance of CIITA-PIV as a therapeutic target for interventional strategies that can manage autoimmune disease and allograft rejection with little interference on the function of professional APCs of the immune system.
我们之前证明，在体外培养中，干扰素α（IFNα）可下调与胰岛相关的人非专职抗原呈递细胞（APCs）中主要组织相容性复合体II类（MHCII）基因的表达。IFNα对专职APCs中的MHCII表达具有相反的作用。在本研究中，我们发现，在人MHCII阳性非专职抗原呈递人非造血细胞系中，IFNα介导的MHCII下调机制是调节细胞因子信号转导的负反馈系统的结果，该系统最终抑制II类反式激活因子（CIITA）基因的启动子III和IV。由于CIITA-PIV异构体主要负责非专职APCs中MHCII基因的组成型表达，我们在体外系统中进行并实现了CIITA-PIV mRNA的特异性敲低，获得了与IFNα相似的MHCII分子部分沉默。我们相信，我们的结果为CIITA-PIV作为一种治疗靶点的潜在意义提供了新的认识，该靶点可用于干预策略，以管理自身免疫性疾病和同种异体移植排斥反应，同时对免疫系统专职APCs的功能干扰很小。
