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MicroRNA-98 and let-7 Confer Cholangiocyte Expression of Cytokine-Inducible Src Homology 2-Containing Protein in Response to Microbial Challenge^1,2

Department of Medical Microbiology and Immunology, Creighton University Medical Center, Omaha, NE 68178

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 IB degradation and regulate NF-B 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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¹ This work was supported by National Institutes of Health Grants AI071321 and by the Nebraska Tobacco Settlement Biomedical Research Program LB692 (to X-M.C).

² The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

³ Address correspondence and reprint requests to Dr. Xian-Ming Chen, Department of Medical Microbiology and Immunology, Creighton University Medical Center, 2500 California Plaza, Omaha, NE 68178. E-mail address: xianmingchen{at}creighton.edu

⁴ Abbreviations used in this paper: CIS, cytokine-inducible Src homology 2-containing protein; SOCS, suppressors of cytokine signaling protein; SH, Src homology; miRNA, microRNA; UTR, untranslated region; HIBEpiC, human intrahepatic biliary epithelial; miR-98, microRNA-98; DN, dominant negative.