title: Cryptosporidium parvum induces SIRT1 expression in host epithelial cells through downregulating let-7i.
abstract: Epithelial cells along human gastrointestinal mucosal surface express pathogen-recognizing receptors and actively participate in the regulation of inflammatory reactions in response to microbial infection. The NAD-dependent deacetylase sirtuin-1 (SIRT1), one member of the sirtuin family of proteins and an NAD-dependent deacetylase has been implicated in the regulation of multiple cellular processes, including inflammation, longevity, and metabolism. In this study, we demonstrated that infection of cultured human biliary epithelial cells (H69 cholangiocytes) with a parasitic protozoan, Cryptosporidium parvum, induced SIRT1 expression at the protein level without a change in SIRT1 mRNA content. Using real-time PCR and Northern blot analyses, we found that C. parvum infection decreased the expression of let-7i in infected H69 cells. Down-regulation of let-7i caused relief of miRNA-mediated translational suppression of SIRT1 and consequently, resulted in an increased SIRT1 protein level in infected H69 cell cultures. Moreover, gain- and loss-of-function studies revealed that let-7i could modulate NF-κB activation through modification of SIRT1 protein expression. Thus, our data suggest that let-7i regulates SIRT1 expression in human biliary epithelial cells in response to microbial challenge, suggesting a new role of let-7i in the regulation of NF-κB-mediated epithelial innate immune response.
authors.affiliation: College of Materials and Chemistry & Chemical Engineering, Chengdu University of Technology, Chengdu 610059, China.
authors.forename: Hongguan
authors.initials: H
authors.lastname: Xie
authors.affiliation: College of Materials and Chemistry & Chemical Engineering, Chengdu University of Technology, Chengdu 610059, China.
authors.forename: Ningfei
authors.initials: N
authors.lastname: Lei
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University Medical Center, Omaha, NE 68178, USA.
authors.forename: Ai-Yu
authors.initials: AY
authors.lastname: Gong
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University Medical Center, Omaha, NE 68178, USA.
authors.forename: Xian-Ming
authors.initials: XM
authors.lastname: Chen
authors.affiliation: College of Materials and Chemistry & Chemical Engineering, Chengdu University of Technology, Chengdu 610059, China. Electronic address: guokuhu@gmail.com.
authors.forename: Guoku
authors.initials: G
authors.lastname: Hu
mesh_terms: D045744:Cell Line, Tumor; D016785:Cryptosporidium parvum / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D005786:Gene Expression Regulation; D006790:Host-Parasite Interactions; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics* / Q000276:immunology
chemical_list: D016209:Interleukin-8; D035683:MicroRNAs; D012333:RNA, Messenger; C487931:mirnlet7 microRNA, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: C. parvum; Epithelium; NF-κB; SIRT1; let-7