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首页> 外文期刊>Cytokine >The TGFβ1 pathway is required for NFκB dependent gene expression in mouse keratinocytes
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The TGFβ1 pathway is required for NFκB dependent gene expression in mouse keratinocytes

机译：在小鼠角质形成细胞中的NFκB依赖性基因表达需要TGFβ1途径

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摘要

The transforming growth factor-beta 1 (TGFβ1) and NFκB pathways are important regulators of epidermal homeostasis, inflammatory responses and carcinogenesis. Previous studies have shown extensive crosstalk between these pathways that is cell type and context dependent, but this has not been well-characterized in epidermal keratinocytes. Here we show that in primary mouse keratinocytes, TGFβ1 induces NFκB-luciferase reporter activity that is dependent on both NFκB and Smad3. TGFβ1-induced NFκB-luciferase activity was blocked by the IκB inhibitor parthenolide, the IκB super-repressor, a dominant negative TGFβ1-activated kinase 1 (TAK1) and genetic deletion of NFκB1. Coexpression of NFκB p50 or p65 subunits enhanced NFκB-luciferase activity. Similarly, inhibition of the TGFβ1 type I receptor with SB431542 or genetic deletion of Smad3 blocked TGFβ1 induction of NFκB-luciferase. TGFβ1 rapidly induced IKK phosphorylation but did not cause a detectable decrease in cytoplasmic IκB levels or nuclear translocation of NFκB subunits, although EMSA showed rapid NFκB nuclear binding activity that could be blocked by SB431542 treatment. TNFα, a well characterized NFκB target gene was also induced by TGFβ1 and this was blocked in NFκB+/- and -/- keratinocytes and by the IκB super-repressor. To test the effects of the TGFβ1 pathway on a biologically relevant activator of NFκB, we exposed mice and primary keratinocytes in culture to UVB irradiation. In primary keratinocytes UVB caused a detectable increase in levels of Smad2 phosphorylation that was dependent on ALK5, but no significant increase in SBE-dependent gene expression. Inhibition of TGFβ1 signaling in primary keratinocytes with SB431542 or genetic deletion of Tgfb1 or Smad3 suppressed UVB induction of TNFα message. Similarly, UVB induction of TNFα mRNA was blocked in skin of Tgfb1+/- mice. These studies demonstrate that intact TGFβ1 signaling is required for NFκB-dependent gene expression in mouse keratinocytes and skin and suggest that a convergence of these pathways in the nucleus rather than the cytoplasm may be critical for regulation of inflammatory pathways in skin by TGFβ1.
机译：转化生长因子-β1（TGFβ1）和NFκB途径是表皮稳态，炎症反应和致癌作用的重要调节因子。以前的研究在这些途径之间显示出广泛的串扰，这些途径是细胞类型和上下文依赖性的，但这并未以表皮角蛋白细胞的特征在一起。在这里，我们表明，在原发性小鼠角质形成细胞中，TGFβ1诱导依赖于NFκB和SMAD3的NFκB-荧光素酶报告活性。 TGFβ1诱导的NFκB-荧光素酶活性被IκB抑制剂疗法，IκB超级阻遏物，优势阴性TGFβ1-活化激酶1（Tak1）和NFκB1的遗传缺失阻断。 NFκBP50或P65亚基的共表达增强了NFκB-荧光素酶活性。类似地，抑制具有SB431542的TGFβ1型I受体或SMAD3的遗传缺失缺陷NFκB-荧光素酶的诱导诱导的SMAD3诱导。 TGFβ1迅速诱导IKK磷酸化，但没有引起可检测的细胞质IκB水平或NFκB子单元核转移的可检测性降低，尽管EMSA显示出通过SB431542治疗阻塞的快速NFκB核结合活性。 TNFα，一种表征良好的NFκB靶基因也被TGFβ1诱导，这在NFκB+/- / - / - / - 角质形成细胞和IκB超级压缩机中封闭。为了测试TGFβ1途径对NFκB的生物相关活化剂的影响，我们将培养物暴露于培养物至UVB辐照。在初级角质形成细胞中，UVB导致依赖于ALK5的SMAD2磷酸化水平的可检测增加，但是依赖于SMBE的基因表达没有显着增加。用Sb431542抑制原发性角质形成细胞的TGFβ1信号传导或TGFB1或SMAD3的遗传缺失抑制TNFα消息的UVB诱导。类似地，TNFαmRNA的UVB诱导在TGFB1 +/-小鼠的皮肤中封闭。这些研究表明，在小鼠角质形成细胞和皮肤中，完整的TGFβ1信号传导是必需的，并且表明核中这些途径的收敛性而不是细胞质可能对TGFβ1调节皮肤中的炎性途径至关重要。

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  • 来源
    《Cytokine》 |2013年第3期|共8页
  • 作者

    HoganK.A.; RavindranA.; PodolskyM.A.; GlickA.B.;

  • 作者单位

    Department of Veterinary and Biomedical Sciences The Pennsylvania State University University;

    Department of Veterinary and Biomedical Sciences The Pennsylvania State University University;

    Department of Veterinary and Biomedical Sciences The Pennsylvania State University University;

    Department of Veterinary and Biomedical Sciences The Pennsylvania State University University;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 细胞生物学;
  • 关键词

    Keratinocyte; NFkappaB; TGFbeta1; TNFalpha; UVB;

    机译：角膜炎;nfkappab;tgfbeta1;tnfalpha;uvb;

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