Counterregulatory effects of interferon-gamma and endotoxin on expression of the human C4 genes.-猫眼课题宝

干扰素-γ和内毒素对人类 C4 基因表达的反调节作用。

DOI：

10.1172/jci114523

发表时间：

1990

期刊：

The Journal of clinical investigation

影响因子：

通讯作者：

中科院分区：

文献类型：

作者：

Kulics,J;Colten,HR;Perlmutter,DH

自身免疫性疾病的易感性与编码补体蛋白C4的两个基因座之一的无效等位基因相关。这两个基因座C4 A和C4 B在一级结构上高度同源，但编码具有不同功能活性的蛋白质。C4 A和C4 B基因的表达在人肝癌细胞和用相应基因转化的鼠成纤维细胞中由IFN-γ调节。在这些细胞系中，IFN-γ对C4 A的表达的影响显著大于C4 B，且持续时间更长。在这项研究中，我们研究了合成和调节C4 A和C4 B在外周血单核细胞从正常的，C4 A无效，和C4 B无效的个人。人外周血单核细胞中C4的合成随着培养时间的推移而减少。IFN-γ介导正常人单核细胞中C4 mRNA稳态水平的浓度和时间依赖性增加以及C4合成的相应增加。LPS降低单核细胞C4表达，并完全消除IFN-γ对该基因表达的影响。相反，LPS和IFN-γ在上调另一种III类MHC基因产物补体蛋白因子B的表达中具有协同作用。LPS对组成型和IFN-γ调节的C4合成的影响可能不是通过释放内源性单核因子IL-1 β、TNF-α或IL-6介导的。C4的合成以及IFN-γ和LPS对其合成的调节在正常、C4 A-和C4 B-缺失个体中相似。这些结果证明了C4在肝外部位的合成以及C4基因表达的组织特异性调节。图片

Susceptibility to autoimmune disease is associated with null alleles at one of the two genetic loci encoding complement protein C4. These two genetic loci, C4A and C4B, are highly homologous in primary structure but encode proteins with different functional activities. Expression of C4A and C4B genes is regulated by IFN-gamma in human hepatoma cells and in murine fibroblasts transformed with the respective genes. In these cell lines, IFN-gamma has a significantly greater and longer-lasting effect on expression of C4A than that of C4B. In this study we examined synthesis and regulation of C4A and C4B in peripheral blood monocytes from normal, C4A-null, and C4B-null individuals. Synthesis of C4 in human peripheral blood monocytes decreases during time in culture. IFN-gamma mediates a concentration- and time-dependent increase in steady-state levels of C4 mRNA and a corresponding increase in synthesis of C4 in normal human monocytes. LPS decreases monocyte C4 expression and completely abrogates the effect of IFN-gamma on the expression of this gene. In contrast, LPS and IFN-gamma have a synergistic effect in upregulating expression of another class III MHC gene product, complement protein factor B. The effect of LPS on constitutive and IFN-gamma-regulated C4 synthesis is probably not mediated via release of endogenous monokines IL-1 beta, TNF-alpha, or IL-6. Synthesis of C4, and regulation of its synthesis by IFN-gamma and LPS, are similar in normal, C4A-, and C4B-null individuals. These results demonstrate the synthesis of C4 at extrahepatic sites and tissue-specific regulation of C4 gene expression.Images