MicroRNA-98 and let-7 confer cholangiocyte expression of cytokine-inducible Src homology 2-containing protein in response to microbial challenge.
MicroRNA-98 and let-7 confer cholangiocyte expression of cytokine-inducible Src homology 2-containing protein in response to microbial challenge.
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DOI：
10.4049/jimmunol.0804362
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发表时间：
2009-08-01
期刊：
影响因子：
--
通讯作者：
Chen XM
中科院分区：
文献类型：
--
作者：
Hu G;Zhou R;Liu J;Gong AY;Eischeid AN;Dittman JW;Chen XM
MicroRNAs转录后基因调控(MiRNAs)参与了TLR介导的炎症反应的微调。细胞因子诱导的Src同源2蛋白是炎性细胞因子信号转导的重要负性调节因子，属于细胞因子信号转导抑制蛋白家族的一员。利用正常人胆管上皮细胞(胆管细胞)的体外模型，我们证明了内毒素刺激或感染寄生虫微小隐孢子虫可以通过激活TLR信号通路诱导CIS蛋白的表达，而不改变CIS mRNA的水平。在这些在胆管细胞中表达的miRNAs中，我们发现microRNA-98(miR-98)或let-7靶向CIS的3‘非翻译区会导致翻译抑制，但不会导致CIS mRNA的降解。脂多糖刺激或微小弧菌感染可降低胆管细胞miR-98和let-7的表达。MiR-98和let-7的下调缓解了miRNA对CIS的翻译抑制，并促进了内毒素和微小弧菌刺激的CIS蛋白的表达。此外，功能获得(通过CIS的过度表达)和功能丧失(通过siRNA干扰)的研究表明，在内毒素刺激或微小弧菌感染的情况下，CIS可以促进IκBα的降解，并调节NF-κB的激活。我们的数据表明，miR-98和let-7在微生物攻击下诱导CIS的胆管细胞表达，这一过程可能与TLR介导的上皮天然免疫反应的调节有关。
Posttranscriptional gene regulation by microRNAs (miRNAs) has been implicated in the fine-tuning of TLR-mediated inflammatory response. The cytokine-inducible Src homology 2-containing protein (CIS), one member of the suppressors of cytokine signaling family of proteins, is an important negative regulator for inflammatory cytokine signaling. Using in vitro models using normal human biliary epithelial cells (cholangiocytes), we demonstrated that LPS stimulation or infection with the parasitic protozoan Cryptosporidium parvum induced expression of CIS protein without a change in CIS mRNA levels by activating the TLR signaling pathway. Of those miRNAs expressed in cholangiocytes, we found that targeting of the 3′-untranslated region of CIS by microRNA-98 (miR-98) or let-7 resulted in translational repression, but not CIS mRNA degradation. LPS stimulation or C. parvum infection decreased cholangiocyte expression of miR-98 and let-7. Down-regulation of miR-98 and let-7 relieved miRNA-mediated translational suppression of CIS and contributed to LPS- and C. parvum-stimulated CIS protein expression. Moreover, gain-of-function (by overexpression of CIS) and loss-of-function (by siRNA interference) studies revealed that CIS could enhance IκBα degradation and regulate NF-κB activation in cholangiocytes in response to LPS stimulation or C. parvum infection. Our data suggest that miR-98 and let-7 confer cholangiocyte expression of CIS in response to microbial challenge, a process that may be relevant to the regulation of TLR-mediated epithelial innate immune response.
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影响因子：
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