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

• Published in: PloS one 2013-05, Vol.8 (5), p.e65153-e65153
• Main Authors: Zhou, Rui, Gong, Ai-Yu, Chen, Dongqing, Miller, Ryan E, Eischeid, Alex N, Chen, Xian-Ming
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions - genetics; Acetylation; Adaptive immunity; Animals; Antiinfectives and antibacterials; Antimicrobial peptides; Base Sequence; Biliary Tract - pathology; Biology; CCAAT-Enhancer-Binding Protein-beta - metabolism; Cell Line; Chemokine CX3CL1 - metabolism; Chemokines; Chromatin; Chromatin remodeling; Cryptosporidiosis - genetics; Cryptosporidiosis - microbiology; Cryptosporidiosis - pathology; Cryptosporidium; Cryptosporidium parvum; Cryptosporidium parvum - physiology; CX3C Chemokine Receptor 1; CX3CR1 protein; Cytokines; DEAD-box RNA Helicases - metabolism; Down-Regulation - genetics; Effector cells; Epithelial cells; Epithelial Cells - enzymology; Epithelial Cells - microbiology; Epithelial Cells - pathology; Gallbladder; Gene expression; Genetic engineering; Histone deacetylase; Histone Deacetylases - metabolism; Histones - metabolism; Humans; Immune system; Immunity; Immunology; Infections; Infiltration; Inflammation; Laboratory animals; Lipopolysaccharides; Medicine; Mice; Mice, Inbred C57BL; Microorganisms; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Molecular Sequence Data; Mucosa; NF-kappa B - metabolism; NF-κB protein; Peptides; Promoter Regions, Genetic - genetics; Receptors, Chemokine - metabolism; Ribonuclease III - metabolism; RNA polymerase; Signal Transduction; Signaling; Transcription; Transcription factors; Transcription, Genetic
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0065153

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.