Requirement of hydrogen peroxide generation in TGF-β1 signal transduction in human lung fibroblast cells:: Involvement of hydrogen peroxide and Ca2+ in TGF-β1-induced IL-6 expression
Requirement of hydrogen peroxide generation in TGF-β1 signal transduction in human lung fibroblast cells:: Involvement of hydrogen peroxide and Ca2+ in TGF-β1-induced IL-6 expression
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DOI：
10.4049/jimmunol.165.4.2190
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发表时间：
2000-08-15
影响因子：
4.4
通讯作者：
Choi, I
中科院分区：
文献类型：
--
作者：
Junn, E;Lee, KN;Choi, I
转化生长因子-β1刺激人肺成纤维细胞产生一过性氧自由基，作用5min后最大。抗氧化剂N-乙酰-L半胱氨酸、转化生长因子-β1刺激人肺成纤维细胞IL-6基因表达和蛋白质合成可抑制这种氧自由基的增加。抗氧化剂NAC、谷胱甘肽和过氧化氢酶抑制转化生长因子-β1诱导的IL-6基因表达，直接过氧化氢诱导IL-6表达呈剂量依赖关系。NAC还可降低转化生长因子-β1诱导的AP-1结合活性，而AP-1结合活性与IL-6基因表达有关。有报道称，转化生长因子-β1可刺激细胞内钙内流。EGTA抑制转化生长因子-β1或H_2O_2诱导的IL-6表达，离子霉素促进IL-6表达，同时以同样的方式调节AP-1的活性。丝裂原活化蛋白激酶(MAPK)/细胞外信号相关激酶1的抑制剂PD98059可抑制转化生长因子-β1或过氧化氢诱导的IL-6和AP-1的活化。此外，转化生长因子-β1或过氧化氢增加MAPK活性，而该活性被EGTA和NAG降低，提示MAPK参与了转化生长因子-β1诱导的IL-6的表达。综上所述，这些结果表明，转化生长因子-β1诱导细胞内过氧化氢产生一过性增加，从而调节下游事件，如钙离子内流、MAPK、AP-1激活和IL-6基因表达。
Stimulation of human lung fibroblast cells with TGF-beta 1 resulted in a transient burst of reactive oxygen species with maximal increase at 5 min after treatment. This reactive oxygen species increase was inhibited by the antioxidant, N-acetyl-L-cysteine (NAC), TGF-beta 1 treatment stimulated IL-6 gene expression and protein synthesis in human lung fibroblast cells. Antioxidants including NAC, glutathione, and catalase reduced TGF-beta 1-induced IL-6 gene expression, and direct H2O2 treatment induced IL-6 expression in a dose-dependent manner. NAC also reduced TGF-beta 1-induced AP-1 binding activity, which is involved in IL-6 gene expression. It has been reported that Ca2+ influx is stimulated by TGF-beta 1 treatment. EGTA suppressed TGF-beta 1- or H2O2-induced IL-6 expression, and ionomycin increased IL-6 expression, with simultaneously modulating AP-1 activity in the same pattern. PD98059, an inhibitor of mitogen-activated protein kinase (MAPK) kinase/extracellular signal-related kinase kinase 1, suppressed TGF-beta 1- or H2O2-induced IL-6 and AP-1 activation. In addition, TGF-beta 1 or H2O2 increased MAPK activity which was reduced by EGTA and NAG, suggesting that MAPK is involved in TGF-beta 1-induced IL-6 expression. Taken together, these results indicate that TGF-beta 1 induces a transient increase of intracellular H2O2 production, which regulates downstream events such as Ca2+ influx, MAPK, and AP-1 activation and IL-6 gene expression.