Transcriptional activation of the type I collagen genes COL1A1 and COL1A2 in fibroblasts by interleukin-4:: Analysis of the functional collagen promoter sequences
Transcriptional activation of the type I collagen genes COL1A1 and COL1A2 in fibroblasts by interleukin-4:: Analysis of the functional collagen promoter sequences
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DOI：
10.1002/jcp.10395
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发表时间：
2004-02-01
影响因子：
5.6
通讯作者：
Rieber, EP
中科院分区：
文献类型：
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作者：
Büttner, C;Skupin, A;Rieber, EP
肺炎继发肺纤维化是胸部肿瘤放射治疗的常见并发症。这些纤维化病变的一个特点是过度产生和积聚细胞外基质蛋白，如I型胶原。除转化生长因子-β1外，IL-4还被认为是成纤维细胞胶原基因合成的有效诱导剂。本研究分析了IL-4对正常人肺成纤维细胞中α1(I)前胶原(COL1A1)启动子和α2(I)前胶原(COL1A2)启动子的调节作用。我们提供的证据表明，IL-4诱导的转录激活剂STAT6与COL1A1和COL1A2启动子内的各种序列结合。用5‘端缺失的COL1A1和COL1A2启动子与荧光素酶基因融合的报告基因分析这些区域的调控功能。IL-4处理瞬时转导COL1A1启动子缺失构建体的人成纤维细胞的荧光素酶活性比未处理的成纤维细胞高25%，而由COL1A2启动子驱动的荧光素酶活性在IL-4处理后增强约70%。SP1、NFkappaB和STAT6的联合作用主要参与了IL-4介导的COL1A2基因的激活。与反向STAT6共识基序TTC N-3/4 GCT相邻的AP2位点位于转录起始点205个碱基以内，似乎支持IL-4诱导的适度COL1A1基因激活。干扰素-γ对转录的下调主要见于COL1A1启动子。(C)2003年Wiley-Liss，Inc.
Pneumonitis followed by lung fibrosis is a frequent complication of radiation therapy of chest tumors. A hallmark of these fibrotic lesions is the excessive production and accumulation of extracellular matrix proteins such as type I collagen. In addition to TGF-beta1, IL-4 has been recognized as a potent inducer of collagen gene synthesis in fibroblasts. In this study, we analyzed the regulation of the alpha1(I) procollagen (COL1A1) promoter and the alpha2(I) procollagen (COL1A2) promoter by IL-4 in normal human lung fibroblasts. We provide evidence that the IL-4-induced transcriptional activator STAT6 binds to various sequences within the COL1A1 and COL1A2 promoter. The regulatory function of these regions was tested by reporter gene analysis using 5'deletions of the COL1A1 and COL1A2 promoter fused to the luciferase gene. Interleukin-4 treatment of human fibroblasts transiently transfected with COL1A1 promoter deletion constructs resulted in luciferase activity exceeding that of untreated fibroblasts by 25%, while luciferase activity driven by the COL1A2 promoter was enhanced by about 70% upon IL-4 treatment. A combined action of SP1, NFkappaB, and STAT6 essentially contributes to the IL-4 mediated COL1A2 gene activation. An AP2 site adjacent to the reverse orientated STAT6 consensus motif TTC N-3/4 GCT is located within 205 bases from the transcription startsite and seems to support the moderate IL-4-induced COL1A1 gene activation. Interferon-gamma down-regulation of transcription is mainly seen with the COL1A1 promoter. (C) 2003 Wiley-Liss, Inc.