title: Histone deacetylases and NF-kB signaling coordinate expression of CX3CL1 in epithelial cells in response to microbial challenge by suppressing miR-424 and miR-503.
abstract: The NF-kB pathway is key to epithelial immune defense and has been implicated in secretion of antimicrobial peptides, release of cytokines/chemokines to mobilize immune effector cells, and activation of adaptive immunity. The expression of many inflammatory genes following infection involves the remodeling of the chromatin structure. We reported here that histone deacetylases (HDACs) and NF-kB signaling coordinate expression of CX3CL1 in epithelial cells following Cryptosporidium parvum infection. Upregulation of CX3CL1 was detected in cultured human biliary epithelial cells following infection. Expression of miR-424 and miR-503 was downregulated, and was involved in the induction of CX3CL1 in infected cells. C. parvum infection suppressed transcription of the mir-424-503 gene in a NF-kB- and HDAC-dependent manner. Increased promoter recruitment of NF-kB p50 and HDACs, and decreased promoter H3 acetylation associated with the mir-424-503 gene were observed in infected cells. Upregulation of CX3CL1 in biliary epithelial cells and increased infiltration of CX3CR1(+) cells were detected during C. parvum infection in vivo. Induction of CX3CL1 and downregulation of miR-424 and miR-503 were also detected in epithelial cells in response to LPS stimulation. The above results indicate that HDACs and NF-kB signaling coordinate epithelial expression of CX3CL1 to promote mucosal antimicrobial defense through suppression of the mir-424-503 gene.
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, Nebraska, United States of America.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhou
authors.forename: Ai-Yu
authors.initials: AY
authors.lastname: Gong
authors.forename: Dongqing
authors.initials: D
authors.lastname: Chen
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Miller
authors.forename: Alex N
authors.initials: AN
authors.lastname: Eischeid
authors.forename: Xian-Ming
authors.initials: XM
authors.lastname: Chen
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D001659:Biliary Tract / Q000473:pathology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D002460:Cell Line; D054428:Chemokine CX3CL1 / Q000378:metabolism*; D003457:Cryptosporidiosis / Q000235:genetics / Q000382:microbiology / Q000473:pathology; D016785:Cryptosporidium parvum / Q000502:physiology*; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000201:enzymology / Q000382:microbiology* / Q000473:pathology; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D019707:Receptors, Chemokine / Q000378:metabolism; D043244:Ribonuclease III / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D020413:3' Untranslated Regions; D022782:CCAAT-Enhancer-Binding Protein-beta; D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1; C471885:Cx3cr1 protein, mouse; D006657:Histones; C554214:MIRN424 microrna, human; C545473:MIRN503 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D019707:Receptors, Chemokine; C408087:DICER1 protein, human; D043244:Ribonuclease III; D006655:Histone Deacetylases; D053487:DEAD-box RNA Helicases