Entinostat up-regulates the CAMP gene encoding LL-37 via activation of STAT3 and HIF-1α transcription factors.
Entinostat up-regulates the CAMP gene encoding LL-37 via activation of STAT3 and HIF-1α transcription factors.
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DOI：
10.1038/srep33274
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发表时间：
2016-09-16
影响因子：
4.6
通讯作者：
Bergman P
中科院分区：
文献类型：
--
作者：
Miraglia E;Nylén F;Johansson K;Arnér E;Cebula M;Farmand S;Ottosson H;Strömberg R;Gudmundsson GH;Agerberth B;Bergman P
细菌对经典抗生素的耐药性是一个日益严重的问题，新抗生素的开发受到限制。因此，需要新的抗生素替代品。抗菌肽（Antimicrobial peptides，AMP）是天然免疫的效应分子，可由多种化合物诱导，包括维生素D和苯丁酸（phenyl-butyrate，PBA）。利用基于荧光素酶的测定，我们最近发现组蛋白脱乙酰酶抑制剂恩替诺特是编码人凯萨林菌素LL-37的CAMP基因的有效诱导剂。在这里，我们研究了诱导的机制，并且还发现恩替司他上调人β-防御素1。对CAMP启动子序列的分析揭示了转录因子STAT 3和HIF-1α的结合位点。通过使用短发夹RNA和选择性抑制剂，我们发现这两种转录因子都参与了恩替司他诱导的LL-37表达。然而，仅发现HIF-1α被募集到CAMP启动子，表明恩替诺特激活STAT 3，STAT 3通过增加HIF-1α的表达促进CAMP的转录。最后，我们通过显示恩替司他引发的LL-37表达在来自具有STAT 3突变的患者的巨噬细胞中受损，提供了与我们的发现的体内相关性。总之，我们的研究结果支持STAT 3和HIF-1α在调节LL-37表达中的作用。
Bacterial resistance against classical antibiotics is a growing problem and the development of new antibiotics is limited. Thus, novel alternatives to antibiotics are warranted. Antimicrobial peptides (AMPs) are effector molecules of innate immunity that can be induced by several compounds, including vitamin D and phenyl-butyrate (PBA). Utilizing a luciferase based assay, we recently discovered that the histone deacetylase inhibitor Entinostat is a potent inducer of the CAMP gene encoding the human cathelicidin LL-37. Here we investigate a mechanism for the induction and also find that Entinostat up-regulates human β-defensin 1. Analysis of the CAMP promoter sequence revealed binding sites for the transcription factors STAT3 and HIF-1α. By using short hairpin RNA and selective inhibitors, we found that both transcription factors are involved in Entinostat-induced expression of LL-37. However, only HIF-1α was found to be recruited to the CAMP promoter, suggesting that Entinostat activates STAT3, which promotes transcription of CAMP by increasing the expression of HIF-1α. Finally, we provide in vivo relevance to our findings by showing that Entinostat-elicited LL-37 expression was impaired in macrophages from a patient with a STAT3-mutation. Combined, our findings support a role for STAT3 and HIF-1α in the regulation of LL-37 expression.
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影响因子：
3.7
作者：
Cederlund A;Olliver M;Rekha RS;Lindh M;Lindbom L;Normark S;Henriques-Normark B;Andersson J;Agerberth B;Bergman P
通讯作者：
Bergman P
DOI：
10.1186/1476-9255-10-15
发表时间：
2013-04-11
期刊：
Journal of inflammation (London, England)
影响因子：
--
作者：
Liu Q;Liu J;Roschmann KIL;van Egmond D;Golebski K;Fokkens WJ;Wang D;van Drunen CM
通讯作者：
van Drunen CM
影响因子：
4
作者：
Marr, Alexandra K.;Gooderham, William J.;Hancock, Robert E. W.
通讯作者：
Hancock, Robert E. W.
影响因子：
4.8
作者：
Gombart, AF;Borregaard, N;Koeffler, HP
通讯作者：
Koeffler, HP
影响因子：
64.5
作者：
Dang EV;Barbi J;Yang HY;Jinasena D;Yu H;Zheng Y;Bordman Z;Fu J;Kim Y;Yen HR;Luo W;Zeller K;Shimoda L;Topalian SL;Semenza GL;Dang CV;Pardoll DM;Pan F
通讯作者：
Pan F