Kulics J, Colten H R, Perlmutter D H
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110.
J Clin Invest. 1990 Mar;85(3):943-9. doi: 10.1172/JCI114523.
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.
自身免疫性疾病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C4A和C4B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。C4A和C4B基因的表达在人肝癌细胞和用各自基因转化的鼠成纤维细胞中受干扰素-γ调节。在这些细胞系中，干扰素-γ对C4A表达的影响比对C4B的影响显著更大且持续时间更长。在本研究中，我们检测了正常个体、C4A缺失个体和C4B缺失个体外周血单核细胞中C4A和C4B的合成及调节情况。人外周血单核细胞中C4的合成在培养过程中随时间减少。干扰素-γ介导正常人单核细胞中C4 mRNA稳态水平呈浓度和时间依赖性增加以及C4合成相应增加。脂多糖降低单核细胞C4表达并完全消除干扰素-γ对该基因表达的影响。相比之下，脂多糖和干扰素-γ在上调另一类III型主要组织相容性复合体基因产物补体蛋白因子B的表达方面具有协同作用。脂多糖对组成型和干扰素-γ调节的C4合成的影响可能不是通过内源性单核因子IL-1β、TNF-α或IL-6的释放介导的。正常个体、C4A缺失个体和C4B缺失个体中C4的合成及其由干扰素-γ和脂多糖调节的情况相似。这些结果证明了肝外部位C4的合成以及C4基因表达的组织特异性调节。
