Neufeld D S, Lahat N, Graves P, Gillon-Peled M, Kraiem Z, Davies T F
Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029.
Clin Immunol Immunopathol. 1993 May;67(2):151-6. doi: 10.1006/clin.1993.1058.
The induction of HLA class II antigens on human thyroid epithelial cells has been shown to be an intimate part of the pathology of autoimmune thyroid disease and may also be relevant to the natural history of thyroid neoplasia since thyroid cancer cells may show spontaneous HLA class II antigen expression. We have, therefore, analyzed the regulation of HLA-DR-alpha-specific mRNA transcripts, as a model for HLA class II antigen induction, in three established human thyroid cancer cell lines (papillary thyroid cell line NPA, and follicular thyroid cell lines RO-82-W1 and MRO-87-1). Each of the lines expressed 1.4 kb HLA-DR-alpha-specific mRNA transcripts, either constitutively or after cytokine induction, but showed markedly different regulatory characteristics. For example, the induction of HLA-DR alpha mRNA in response to recombinant human interferon-gamma (IFN-gamma) was inversely proportional to the degree of constitutive DR alpha mRNA expression; when there was constitutive absence there was a greater degree of induction. Similarly, the half-lives of the HLA-DR alpha mRNA transcripts varied from 80 to 420 min with the longest degradation time occurring in those cells lacking constitutive expression of HLA-DR alpha mRNA. These data indicated that the degradation rate was not a determinant of their constitutive expression. We also sequenced the 5' promoter region of the HLA-DR alpha gene (nucleotides -88 to -277 with respect to the translation start site) in each of the three cell lines. Sequence analyses revealed identity to the previously published normal human genomic sequence. Taken together, therefore, these data indicate that transactivating factors, rather than changes in mRNA degradation or promoter abnormalities, are the likely causes of variation in constitutive and cytokine-induced HLA-DR alpha gene expression in human thyroid cancer cells.
人甲状腺上皮细胞上HLA II类抗原的诱导已被证明是自身免疫性甲状腺疾病病理学的一个重要部分，并且可能也与甲状腺肿瘤的自然病程相关，因为甲状腺癌细胞可能表现出自发性HLA II类抗原表达。因此，我们分析了三种已建立的人甲状腺癌细胞系（乳头状甲状腺细胞系NPA以及滤泡状甲状腺细胞系RO-82-W1和MRO-87-1）中HLA-DR-α特异性mRNA转录物的调控，以此作为HLA II类抗原诱导的模型。每个细胞系都组成性地或在细胞因子诱导后表达1.4 kb的HLA-DR-α特异性mRNA转录物，但表现出明显不同的调控特征。例如，重组人干扰素-γ（IFN-γ）诱导的HLA-DR α mRNA与组成性DR α mRNA表达程度呈反比；当组成性缺失时，诱导程度更高。同样，HLA-DR α mRNA转录物的半衰期从80分钟到420分钟不等，降解时间最长的发生在那些缺乏HLA-DR α mRNA组成性表达的细胞中。这些数据表明降解速率不是其组成性表达的决定因素。我们还对这三个细胞系中HLA-DR α基因的5'启动子区域（相对于翻译起始位点的核苷酸-88至-277）进行了测序。序列分析显示与先前发表的正常人类基因组序列相同。因此，综合这些数据表明，反式激活因子而非mRNA降解的变化或启动子异常，可能是人类甲状腺癌细胞中组成性和细胞因子诱导的HLA-DR α基因表达差异的原因。
