HUMAN FIBROBLASTS SYNTHESIZE ELEVATED LEVELS OF EXTRACELLULAR-MATRIX PROTEINS IN RESPONSE TO INTERLEUKIN-4
HUMAN FIBROBLASTS SYNTHESIZE ELEVATED LEVELS OF EXTRACELLULAR-MATRIX PROTEINS IN RESPONSE TO INTERLEUKIN-4
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DOI：
10.1172/jci116015
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发表时间：
1992-10-01
影响因子：
15.9
通讯作者：
RAGHOW, R
中科院分区：
文献类型：
--
作者：
POSTLETHWAITE, AE;HOLNESS, MA;RAGHOW, R
白介素4(又称B细胞刺激因子-1)是一种由T淋巴细胞和肥大细胞产生的细胞因子，可在体外刺激人真皮成纤维细胞合成细胞外基质蛋白I型和III型胶原和纤维连接蛋白。从类风湿性关节炎和骨关节炎患者获得的几种成纤维细胞滑膜细胞系中也显示了人重组IL-4对胶原的刺激作用。兔抗hrIL-4免疫球蛋白可特异性地中和hrIL-4对成纤维细胞胶原合成的刺激作用。IL-4特异性增加I型和III型前胶原和纤维连接蛋白mRNAs的稳态水平，但对胞浆β-肌动蛋白mRNAs无影响。IL-4处理的成纤维细胞中Proα1(I)胶原转录本的定量分析也得到了反义RNA-mRNA杂交和核糖核酸酶抗性杂交的证实，表明IL-4处理的成纤维细胞表达更高水平的Proα1(I)胶原转录本。核径流转录实验表明，IL-4促进了mRNA的生物合成。根据这些观察，我们得出结论，IL-4在翻译前水平对胶原和纤维连接蛋白的合成起作用，导致这些细胞外基质蛋白的合成。这些和其他数据表明，IL-4可能是一种“纤维化细胞因子”，可能在促进细胞外基质蛋白在正常伤口愈合和病理性纤维化中的生物发生中发挥重要作用，其中肥大细胞和T淋巴细胞在其中发挥核心作用。
Interleukin 4 (also known as "B cell stimulatory factor-1"), a cytokine product of T lymphocytes and mast cells, stimulates synthesis of the extracellular matrix proteins, types I and III collagen and fibronectin, by human dermal fibroblasts in vitro. Stimulation of collagen by human recombinant (hr)IL-4 was also demonstrated in several fibroblastic synovial cell lines obtained from patients with rheumatoid arthritis and osteoarthritis. The stimulatory effect of hrIL-4 on fibroblast collagen synthesis was specifically neutralized by rabbit anti-hrIL-4 Ig. IL-4 specifically increased the steady-state levels of types I and III procollagen and fibronectin mRNAs, with no effect on cytoplasmic beta-actin mRNA. Quantitative analysis of the levels of Pro alpha1 (I) collagen transcripts in IL-4-treated fibroblast cultures was also corroborated by antisense RNA-mRNA hybridization and RNAse resistant hybrids which showed that IL-4-treated fibroblasts expressed higher levels of Pro alpha1 (I) collagen transcripts. Nuclear run-off transcription experiments indicated that IL-4 stimulated the rates of mRNA biogenesis. Based on these observations we conclude that IL-4 exerts its effect on collagen and fibronectin synthesis at the pretranslational level, resulting in synthesis of these extracellular matrix proteins. These and other data suggest that IL-4 may be a "fibrogenic cytokine" that could be important in promoting biogenesis of extracellular matrix proteins in normal wound healing and in pathological fibrosis in which mast cells and T lymphocytes play a central role.