Tumor necrosis factor α suppresses the induction of connective tissue growth factor by transforming growth factor-β in normal and scleroderma fibroblasts
Tumor necrosis factor α suppresses the induction of connective tissue growth factor by transforming growth factor-β in normal and scleroderma fibroblasts
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DOI：
10.1074/jbc.275.20.15220
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发表时间：
2000-05-19
影响因子：
4.8
通讯作者：
Leask, A
中科院分区：
文献类型：
--
作者：
Abraham, DJ;Xu, SW;Leask, A
结缔组织生长因子（CTGF）在多种纤维化疾病中过度表达，推测继发于转化生长因子-β（TGF-β）的活化和产生，转化生长因子-β是成纤维细胞增殖和基质合成的关键诱导物。CTGF基因启动子具有TGF-β反应元件，其调节其在成纤维细胞中的表达，但不调节上皮细胞或淋巴细胞中的表达。最近的研究表明，巨噬细胞产生的细胞因子肿瘤坏死因子α（TNF α）是必要的，以促进炎症和诱导基因，如基质金属蛋白酶，参与伤口愈合的早期阶段，在这项研究中，我们检查的能力，TNF α调节CTGF基因表达。发现TNF α抑制TGF-β诱导的CTGF蛋白在培养的正常成纤维细胞中的表达。TNF-α的活性被NF-κ B抑制剂阻断。我们发现CTGF启动子的-244和-166之间的序列是TGF-β和TNF α调节CTGF表达所必需的。存在硬皮病成纤维细胞的组成型CTGF表达，其通过TGF-β处理而增加。尽管TNF α能够抑制正常和硬皮病皮肤成纤维细胞中TGF-β诱导的CTGF和胶原合成，但从硬皮病患者培养的成纤维细胞对TNF α更具抗性，因为TNF α不能抑制硬皮病成纤维细胞中CTGF表达的基础水平。因此，我们怀疑硬皮病成纤维细胞中组成型CTGF的高水平表达及其对负调节细胞因子的无反应性可能导致硬皮病患者皮肤和内部器官的过度瘢痕形成。
Connective tissue growth factor (CTGF) is over-expressed in a variety of fibrotic disorders, presumably secondary to the activation and production of transforming growth factor-p (TGF-P), a key inducer of fibroblast proliferation and matrix synthesis. The CTGF gene promoter has a TGF-P response element that regulates its expression in fibroblasts but not epithelial cells or lymphocytes. Recent studies have shown that the macrophage-produced cytokine tumor necrosis factor alpha (TNF alpha) is necessary to promote inflammation and to induce genes, such as matrix metalloproteinases, involved with the early stages of wound healing, In this study, we examined the ability of TNF alpha to modulate CTGF gene expression. TNF alpha was found to suppress the TGF-beta-induced expression of CTGF protein in cultured normal fibroblasts. The activity of TNF alpha was blocked by NF-kappa B inhibitors. We showed that sequences between -244 and -166 of the CTGF promoter were necessary for both TGF-beta and TNF alpha to modulate CTGF expression. There was a constitutive expression of CTGF by scleroderma fibroblasts that was increased by TGF-beta treatment, Although TNF alpha was able to repress TGF-beta-induced CTGF and collagen synthesis both in normal and scleroderma skin fibroblasts, fibroblasts cultured from scleroderma patients were more resistant to TNF alpha as TNF alpha was unable to suppress the basal level of CTGF expression in scleroderma fibroblasts, Thus, we suspect that the high level of constitutive CTGF expression in scleroderma fibroblasts and its inability to respond to negative regulatory cytokines may contribute to the excessive scarring of skin and internal organs in patients with scleroderma.