TNF-α suppresses α-smooth muscle actin expression in human dermal fibroblasts:: An implication for abnormal wound healing
TNF-α suppresses α-smooth muscle actin expression in human dermal fibroblasts:: An implication for abnormal wound healing
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DOI：
10.1038/sj.jid.5700890
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发表时间：
2007-11-01
影响因子：
6.5
通讯作者：
Garner, Warren L.
中科院分区：
文献类型：
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作者：
Goldberg, Mytien T.;Han, Yuan-Ping;Garner, Warren L.
异常伤口愈合包括从慢性伤口到增生性瘢痕的广泛范围。这两种情况都与伤口床中的异常细胞因子谱相关。在这项研究中，我们试图了解肌成纤维细胞分化和组织生长因子-β（TGF-β）和肿瘤坏死因子-α（TNF-α）刺激下的胶原基质的机械性能之间的动态关系。我们发现TGF-β增加α-平滑肌肌动蛋白（α-SMA），TNF-α单独降低基础α-SMA表达。当同时加入TGF-β 1和TNF-α时，α-SMA表达被抑制到基线以下。实时PCR显示TNF-α在mRNA水平抑制TGF-β 1诱导的肌成纤维细胞（纤维增生）表型基因，例如α-SMA、1A型胶原和纤连蛋白。TNF-α通过影响mRNA稳定性来抑制TGF-β 1诱导的基因表达。我们的研究结果进一步表明，TNF-α抑制TGF-β 1诱导的Smad-3磷酸化通过Jun N-末端激酶信号。机械测试表明，TNF-α在培养5天后降低了晶格的刚度和收缩。我们提出α-SMA、胶原和纤连蛋白表达的变化导致胶原基质的收缩和硬度降低。因此，伤口中细胞因子的平衡决定了细胞外基质的机械性质和最佳伤口愈合。
Abnormal wound healing encompasses a wide spectrum, from chronic wounds to hypertrophic scars. Both conditions are associated with an abnormal cytokine profile in the wound bed. In this study, we sought to understand the dynamic relationships between myofibroblast differentiation and mechanical performance of the collagen matrix under tissue growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha) stimulation. We found TGF-beta increased alpha-smooth muscle actin (alpha-SMA) and TNF-alpha alone decreased the basal alpha-SMA expression. When TGF-beta 1 and TNF-alpha were both added, the alpha-SMA expression was suppressed below the baseline. Real-time PCR showed that TNF-alpha suppresses TGF-beta 1-induced myofibroblast (fibroproliferative) phenotypic genes, for example, alpha-SMA, collagen type 1A, and fibronectin at the mRNA level. TNF-alpha suppresses TGF-beta 1- induced gene expression by affecting its mRNA stability. Our results further showed that TNF-alpha inhibits TGF-beta 1- induced Smad-3 phosphorylation via Jun N-terminal kinase signaling. Mechanical testing showed that TNF-alpha decreases the stiffness and contraction of the lattices after 5 days in culture. We proposed that changes in alpha-SMA, collagen, and fibronectin expression result in decreased contraction and stiffness of collagen matrices. Therefore, the balance of cytokines in a wound defines the mechanical properties of the extracellular matrix and optimal wound healing.