Expression of the heparan sulfate-degrading enzyme heparanase is induced in infiltrating CD4+ T cells in experimental autoimmune encephalomyelitis and regulated at the level of transcription by early growth response gene 1
Expression of the heparan sulfate-degrading enzyme heparanase is induced in infiltrating CD4+ T cells in experimental autoimmune encephalomyelitis and regulated at the level of transcription by early growth response gene 1
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DOI：
10.1189/jlb.0507315
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发表时间：
2007-11-01
影响因子：
5.5
通讯作者：
Hulett, Mark D.
中科院分区：
文献类型：
--
作者：
de Mestre, Amanda M.;Staykova, Maria A.;Hulett, Mark D.
硫酸乙酰肝素裂解酶乙酰肝素酶（HPSE）在炎症过程中基底膜和细胞外基质的重塑中起重要作用。已报道白细胞中可诱导HPSE酶活性;然而，对炎症性疾病期间调节HPSE基因表达的分子机制知之甚少。在这项研究中，HPSE的表达和调节T细胞介导的疾病模型，实验性自身免疫性脑脊髓炎（EAE），进行了研究。表达分析表明，HPSE mRNA诱导大鼠CD 4+抗原特异性T淋巴细胞活化后，与致脑炎的细胞。在大鼠活动性EAE的整个进展过程中对HPSE的动力学和细胞类型特异性表达的检查表明，HPSE在临床疾病期间在浸润中枢神经系统（CNS）的CD 4 + T细胞中高度表达。在疾病进展期间，在CD 8 + T细胞、巨噬细胞或星形胶质细胞中观察到很少或没有HPSE表达。为了研究T细胞中诱导型HPSE基因调控的机制，研究扩展到人原代T细胞。激活后诱导HPSE mRNA、蛋白质和酶活性。对人HPSE启动子的功能分析鉴定了EGRI结合基序，其含有高诱导活性并被EGRI反式激活。此外，用EGRI siRNA处理原代T淋巴细胞抑制诱导型HPSE mRNA表达。这些数据提供的证据表明，诱导HPSE在原代T淋巴细胞的表达在转录水平上的EGRI调节，并在促进CD 4 + T细胞浸润到中枢神经系统，促进EAE是重要的。
The heparan sulfate-cleaving enzyme heparanase (HPSE) plays an important role in remodeling of the basement membrane and extracellular matrix during inflammation. Inducible HPSE enzymatic activity has been reported in leukocytes; however, little is known of the molecular mechainisms that regulate HPSE gene expression during inflammatory disease. In this study, HPSE expression and regulation in the T cell-mediated disease model, experimental antoimmune encephalomyelitis (EAE), were investigated. Expression analysis showed that HPSE mRNA is induced in rat CD4+ antigen-specific T lymphocytes upon activation and correlates with the encephalitogenicity of the cells. Examination of the kinetics and cell type-specific expression of HPSE throughout the progression of active EAE in rats, indicated that HPSE was highly expressed in CD4+ T cells infiltrating the central nervous system (CNS) during clinical disease. Little or no HPSE expression was observed in CD8+ T cells, macrophages, or astrocytes during disease progression. To investigate the mechanism of inducible HPSE gene regulation in T cells, studies were extended into human primary T cells. HPSE mRNA, protein, and enzymatic activity were induced upon activation. Functional analysis of the human HPSE promoter identified an EGRI binding motif that contained high inducible activity and was transactivated by EGRI. Furthermore, the treatment of primary T lymphocytes with an EGRI siRNA inhibited inducible HPSE mRNA expression. These data provide evidence to suggest that inducible HPSE expression in primary T lymphocytes is regulated at the transcriptional level by EGRI and is important in facilitating CD4+ T cell infiltration into the CNS to promote EAE.