TNF‐α represses connexin43 expression in hacat keratinocytes via activation of JNK signaling
TNF‐α represses connexin43 expression in hacat keratinocytes via activation of JNK signaling
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DOI：
10.1002/jcp.21412
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发表时间：
2008-08
影响因子：
5.6
通讯作者：
Chalotte Tacheau;J. Laboureau;A. Mauviel;F. Verrecchia
中科院分区：
文献类型：
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作者：
Chalotte Tacheau;J. Laboureau;A. Mauviel;F. Verrecchia
我们使用药理学和基因敲除方法来阐明Jun-N末端激酶和肿瘤坏死因子-κ下游的核因子αB通路在连接蛋白43(Cx43)基因表达中所起的特定作用。我们证明了肿瘤坏死因子-α在蛋白和基因水平以及转录水平上降低了Cx43在HaCat细胞系中的表达。我们还证明，肿瘤坏死因子-α减少了哈卡特细胞之间的缝隙连接细胞间通讯。使用NFκB信号通路的药物抑制剂，我们确定了NFκB信号通路与肿瘤坏死因子-α对Cx43表达的影响以及随后的GJIC值的降低无关。相反，在NEMO-κ成纤维细胞中，缺乏NF-−活性并不影响κ-α对Cx43表达和细胞间隙连接的影响。相反，药物抑制JNK可取消肿瘤坏死因子-α对HACAT细胞间Cx43基因表达和GJIC的抑制。利用JNK1−/−-JNK2−/−(JNK2−/−)成纤维细胞，我们证明了类似的调控机制也发生在成纤维细胞中。综上所述，这些结果证实JNK而不是NFκB是肿瘤坏死因子-α抑制Cx43基因表达的关键介质。J.细胞。物理。216：438-444,2008。©2008 Wiley-Liss，Inc.
We used both pharmacological and gene knockout approaches to elucidate the specific roles played by the Jun‐N‐terminal kinase (JNK) and NFκB pathways downstream of TNF‐α in the context of connexin43 (Cx43) gene expression. We demonstrate that TNF‐α reduces the expression of Cx43 in HaCat cell lines at the protein and mRNA levels, and transcriptionally. We also demonstrate that TNF‐α decreases gap junctional intercellular communication (GJIC) between HaCat cells. Using pharmacological inhibitors of the NFκB signaling pathway, we determined that the NFκB signaling cascade is not implicated in TNF‐α effect on Cx43 expression and in the subsequent decrease of GJIC. Conversely, in NFκB essential modulator (NEMO−) fibroblasts, lack of NFκB activation did not influence both the effect of TNF‐α on Cx43 expression and on GJIC. In contrast, pharmacologic inhibition of JNK abolishes TNF‐α‐driven repression of Cx43 gene expression and GJIC between HaCat cells. Using JNK 1−/− ‐JNK 2−/− (JNK−/−) fibroblasts, we demonstrate that similar regulatory mechanisms take place in fibroblasts. Together, these results identify JNK and not NFκB, as a critical mediator of TNF‐α repressory effect on Cx43 gene expression. J. Cell. Physiol. 216: 438–444, 2008. © 2008 Wiley‐Liss, Inc.