MicroRNA-155 Regulates Inflammatory Cytokine Production in Tumor-associated Macrophages via Targeting C/EBPβ
MicroRNA-155 Regulates Inflammatory Cytokine Production in Tumor-associated Macrophages via Targeting C/EBPβ
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DOI：
10.1038/cmi.2009.45
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发表时间：
2009-10-01
影响因子：
24.1
通讯作者：
Zheng, Limin
中科院分区：
文献类型：
--
作者：
He, Min;Xu, Zhenqun;Zheng, Limin
巨噬细胞（M phi）是实体瘤的重要组成部分，在不同的微环境中表现出不同的表型。我们最近发现肿瘤可以改变M phi的正常发育过程，从而触发单核细胞的瞬时激活，但其潜在的调控机制尚不完全清楚。在这里，我们发现，转录因子C/EBP β的蛋白表达显着升高，在肿瘤相关的M phi在体外和人类肿瘤原位。C/EBP β蛋白的表达与肿瘤激活的单核细胞中细胞因子的产生相关。此外，我们发现C/EBP β表达在转录后水平受到调节，并与肿瘤激活的单核细胞中microRNA-155（miR-155）的持续减少相关。生物信息学分析显示C/EBP β是miR-155的潜在靶点，荧光素酶测定证实miR-155通过与C/EBP β mRNA的3 'UTR相互作用抑制C/EBP β翻译。进一步的分析表明，miR-155的诱导抑制了肿瘤活化单核细胞中C/EBP β蛋白的表达以及细胞因子的产生，这种作用可以通过沉默C/EBP β来模拟。这些结果表明，肿瘤环境导致单核细胞/M phi中miR-155的持续减少，这进而通过释放转录因子C/EBP β的翻译抑制来调节单核细胞/M phi的功能活性。细胞与分子免疫学2009;6（5）：343-352.
Macrophages (M phi) are prominent components of solid tumors and exhibit distinct phenotypes in different microenvironments. We have recently found that tumors can alter the normal developmental process of M phi to trigger transient activation of monocytes, but the underlying regulatory mechanisms are incompletely understood. Here, we showed that the protein expression of transcription factor C/EBP beta was markedly elevated in tumor-associated M phi both in vitro and human tumors in situ. The expression of C/EBP beta protein correlated with cytokine production in tumor-activated monocytes. Moreover, we found that C/EBP beta expression was regulated at the post-transcriptional level and correlated with sustained reduction of microRNA-155 (miR-155) in tumor-activated monocytes. Bioinformatic analysis revealed that C/EBP beta is a potential target of miR-155 and luciferase assay confirmed that C/EBP beta translation is suppressed by miR-155 through interaction with the 3'UTR of C/EBP beta mRNA. Further analysis showed that induction of miR-155 suppressed C/EBP beta protein expression as well as cytokine production in tumor-activated monocytes, an effect which could be mimicked by silencing of C/EBP beta. These results indicate that tumor environment causes a sustained reduction of miR-155 in monocytes/M phi which in turn regulates the functional activities of monocytes/M phi by releasing the translational inhibition of transcription factor C/EBP beta. Cellular & Molecular Immunology. 2009;6(5):343-352.