FGF-2, IL-1β and TGF-β regulate fibroblast expression of S100A8
FGF-2, IL-1β and TGF-β regulate fibroblast expression of S100A8
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DOI：
10.1111/j.1742-4658.2005.04703.x
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发表时间：
2005-06-01
期刊：
影响因子：
5.4
通讯作者：
Geczy, CL
中科院分区：
文献类型：
--
作者：
Rahimi, F;Hsu, K;Geczy, CL
生长因子，包括成纤维细胞生长因子-2（FGF-2）和转化生长因子-β（TGF-β）调节成纤维细胞功能、分化和增殖。S100 A8和S100 A9是钙结合蛋白S100家族的成员，现在被认为是炎症的标志物。它们由人/鼠伤口中的角质形成细胞和炎性细胞以及由适当活化的巨噬细胞、内皮细胞、上皮细胞和体外角质形成细胞表达。在这项研究中，S100 A8和S100 A9的调节和表达的成纤维细胞进行了检查。内毒素（LPS）、干扰素γ（IFN γ）、肿瘤坏死因子（TNF）和TGF-β在鼠成纤维细胞中不诱导S100 A8基因，而FGF-2在12小时后最大程度地诱导mRNA。FGF-2反应强烈增强，肝素延长。白细胞介素-1 β（IL-1 β）单独或与FGF-2/肝素协同作用强烈诱导3 T3成纤维细胞中的基因。S100 A9 mRNA在任何条件下都不被诱导。在不存在S100 A9的情况下，在原代成纤维细胞中证实了S100 A8的诱导。FGF-2和IL-1 β对S100 A8 mRNA的诱导部分依赖于丝裂原活化蛋白激酶途径，并依赖于新蛋白的合成。S100 A8基因启动子中的FGF-2响应元件与IL-1 β响应元件不同。TGF-β显著抑制FGF-2-/肝素诱导的反应，但不抑制IL-1 β诱导的反应，这可能是由mRNA稳定性降低介导的。S100 A8在活化的成纤维细胞中主要位于胞浆内。大鼠皮肤伤口含有大量的S100 A8阳性成纤维细胞样细胞损伤后2和4天，数量下降了7天。S100 A8通过FGF-2/IL-1 β上调，通过TGF-β下调，以及其在伤口成纤维细胞中的时间依赖性表达表明在炎症和修复部位的成纤维细胞分化中的作用。
Growth factors, including fibroblast growth factor-2 (FGF-2) and transforming growth factor-beta (TGF-beta) regulate fibroblast function, differentiation and proliferation. S100A8 and S100A9 are members of the S100 family of Ca2+-binding proteins and are now accepted as markers of inflammation. They are expressed by keratinocytes and inflammatory cells in human/murine wounds and by appropriately activated macrophages, endothelial cells, epithelial cells and keratinocytes in vitro. In this study, regulation and expression of S100A8 and S100A9 were examined in fibroblasts. Endotoxin (LPS), interferon gamma (IFN gamma), tumour-necrosis factor (TNF) and TGF-beta did not induce the S100A8 gene in murine fibroblasts whereas FGF-2 induced mRNA maximally after 12 h. The FGF-2 response was strongly enhanced and prolonged by heparin. Interleukin-1 beta (IL-1 beta) alone, or in synergy with FGF-2/heparin strongly induced the gene in 3T3 fibroblasts. S100A9 mRNA was not induced under any condition. Induction of S100A8 in the absence of S100A9 was confirmed in primary fibroblasts. S100A8 mRNA induction by FGF-2 and IL-1 beta was partially dependent on the mitogen-activated-protein-kinase pathway and dependent on new protein synthesis. FGF-2-responsive elements were distinct from the IL-1 beta-responsive elements in the S100A8 gene promoter. FGF-2-/heparin-induced, but not IL-1 beta-induced responses were significantly suppressed by TGF-beta, possibly mediated by decreased mRNA stability. S100A8 in activated fibroblasts was mainly intracytoplasmic. Rat dermal wounds contained numerous S100A8-positive fibroblast-like cells 2 and 4 days post injury; numbers declined by 7 days. Up-regulation of S100A8 by FGF-2/IL-1 beta, down-regulation by TGF-beta, and its time-dependent expression in wound fibroblasts suggest a role in fibroblast differentiation at sites of inflammation and repair.