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首页> 外文期刊>Journal of Cellular Physiology >Inhibition of collagen gene expression by interferon-gamma: novel role of the CCAAT/enhancer binding protein beta (C/EBPbeta).
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Inhibition of collagen gene expression by interferon-gamma: novel role of the CCAAT/enhancer binding protein beta (C/EBPbeta).

机译：抑制胶原蛋白的基因表达移行细胞:小说的角色CCAAT /增强子结合蛋白β(C / EBPbeta)。

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By inhibiting collagen synthesis, interferon-gamma (IFN-gamma) plays a key role in maintaining connective tissue homeostasis, but the mechanisms are not well-understood. In addition to intracellular signaling through the canonical JAK-STAT transduction pathway, IFN-gamma was recently shown to regulate gene expression via the CCAAT/enhancer-binding protein beta (C/EBPbeta) as well. Because C/EBPbeta is a crucial mediator of immune and inflammatory responses, and has been implicated in regulation of collagen synthesis by tumor necrosis factor-alpha, we examined its role in the inhibitory effects of IFN-gamma. The results demonstrated that IFN-gamma caused increased C/EBPbeta expression in dermal fibroblasts and enhanced its binding to cognate DNA sequences in the alpha2(I) procollagen gene (COL1A2) promoter in vitro and in vivo. Disruption of C/EBP binding by deletion or site-directed mutagenesis abrogated the inhibition of collagen promoter activity in transient transfection assays, as did cotransfection with dominant negative C/EBPbeta, indicating a functional role of cellular C/EBPbeta in mediating the IFN-gamma response. Rapid phosphorylation of the ERK1/2 MAP kinases induced by IFN-gamma was accompanied by phosphorylation and nuclear translocation of cellular C/EBPbeta, and pretreatment of fibroblasts with ERK1/2 kinase inhibitor blocked C/EBPbeta phosphorylation, as well as inhibition of COL1A2 promoter activity, elicited by IFN-gamma. These results provide compelling evidence for a novel C/EBPbeta-dependent IFN-gamma signaling pathway responsible for inhibition of collagen gene transcription. Taken together with recent reports, the findings indicate that intracellular pathways mediating negative regulation of collagen synthesis in response to distinct inflammatory signals that converge on C/EBPbeta.
机译：通过抑制胶原合成、移行(IFN-gamma)在维护中发挥着关键作用结缔组织内稳态,但机制不容易理解的。胞内信号通过规范化JAK-STAT转导通路,IFN-gamma最近通过调节基因的表达CCAAT / enhancer-binding蛋白质β(C / EBPbeta)。免疫和炎症的重要中介反应,涉及监管肿瘤坏死的胶原蛋白合成因子-α,我们检查了它的作用IFN-gamma抑制的影响。证明IFN-gamma增加引起的在真皮成纤维细胞和C / EBPbeta表达式增强其绑定同源的DNA序列alpha2(我)胶原基因启动子(COL1A2)在体外和体内。通过删除或定点诱变废除了抑制胶原蛋白启动子活动在瞬时转染化验,一样与显性负C / EBPbeta cotransfection,指示功能细胞的作用C / EBPbeta调停IFN-gamma响应。快速ERK1/2 MAP激酶的磷酸化引起IFN-gamma陪同磷酸化和核易位细胞C / EBPbeta和预处理成纤维细胞与ERK1/2激酶抑制剂屏蔽C / EBPbeta磷酸化,抑制COL1A2子活动引起的IFN-gamma。一种新型C / EBPbeta-dependent的证据IFN-gamma信号通路负责抑制胶原蛋白基因转录。加上最近的报告,调查结果表明细胞内途径调解负调节胶原蛋白合成应对不同的炎症信号在C / EBPbeta收敛。

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