Kruppel-like Transcription Factor 6 Regulates Inflammatory Macrophage Polarization
Kruppel-like Transcription Factor 6 Regulates Inflammatory Macrophage Polarization
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DOI：
10.1074/jbc.m113.526749
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发表时间：
2014-04-11
影响因子：
4.8
通讯作者：
Mahabeleshwar, Ganapati H.
中科院分区：
文献类型：
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作者：
Date, Dipali;Das, Riku;Mahabeleshwar, Ganapati H.
背景：巨噬细胞极化调节人类炎性疾病。结果：KLF6是一种新的巨噬细胞极化转录调控因子。结论：KLF6通过调节NF-B和PPAR的功能调控巨噬细胞炎症基因的表达。意义：调节KLF6信号的药物可能在炎症性疾病的治疗中获得治疗增益。越来越多的证据支持巨噬细胞可塑性在健康和疾病中广泛的生物过程中的重要性。调控巨噬细胞极化的主要调控位点在转录水平，近年来已经阐明了几种主要的调控途径。在这项研究中，我们发现kruppel样转录因子6 （KLF6）是控制巨噬细胞物种形成的分子开关。人和小鼠巨噬细胞中，促炎M1刺激（如LPS和IFN-）强烈诱导KLF6表达，M2刺激（如IL4和IL-13）强烈抑制KLF6表达。功能获得和功能丧失的研究表明，KLF6是lps诱导的促炎基因最佳表达所必需的，它与NF-B协同作用。此外，KLF6通过负调控巨噬细胞中过氧化物酶体增殖物激活受体的表达来抑制抗炎基因的表达。总之，这些观察结果表明KLF6是巨噬细胞极化的一种新的转录调节因子。
Background: Macrophage polarization regulates human inflammatory disorders. Results: KLF6 is a novel transcriptional regulator of macrophage polarization. Conclusion: KLF6 regulates macrophage inflammatory gene expression by modulating functions of NF-B and PPAR. Significance: Pharmacological agents that modulate KLF6 signaling may allow for therapeutic gain in the treatment of inflammatory disorders.Accumulating evidence supports the importance of macrophage plasticity in a broad spectrum of biological processes operative in health and disease. A major locus of control regulating macrophage polarization is at the transcriptional level, and several major pathways have been elucidated in recent years. In this study, we identify the Kruppel-like transcription factor 6 (KLF6) as a molecular toggle controlling macrophage speciation. KLF6 expression was robustly induced by pro-inflammatory M1 stimuli (e.g. LPS and IFN-) and strongly suppressed by M2 stimuli (e.g. IL4 and IL-13) in human and murine macrophages. Gain- and loss-of-function studies suggest that KLF6 is required for optimal LPS-induced pro-inflammatory gene expression, acting cooperatively with NF-B. Furthermore, KLF6 inhibits anti-inflammatory gene expression by negatively regulating peroxisome proliferator-activated receptor expression in macrophages. Collectively, these observations identify KLF6 as a novel transcriptional regulator of macrophage polarization.