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      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

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          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.

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          Author and article information

          Contributors
          Role: Editor
          Journal
          PLoS One
          PLoS ONE
          plos
          plosone
          PLoS ONE
          Public Library of Science (San Francisco, USA )
          1932-6203
          2013
          28 May 2013
          : 8
          : 5
          : e65153
          Affiliations
          [1]Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, Nebraska, United States of America
          Technion-Israel Institute of Technology Haifa 32000 Israel., Israel
          Author notes

          Competing Interests: The authors have declared that no competing interests exist.

          Conceived and designed the experiments: RZ AYG XMC. Performed the experiments: RZ AYG DC REM ANE. Analyzed the data: RZ AYG XMC. Wrote the paper: RZ AYG REM XMC.

          Article
          PONE-D-13-08128
          10.1371/journal.pone.0065153
          3665534
          23724129
          a947c17d-9ef8-4a07-91e3-267929ae4353
          Copyright @ 2013

          This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

          History
          : 23 February 2013
          : 22 April 2013
          Page count
          Pages: 11
          Funding
          This project was supported by the National Institutes of Health Grant R01 AI071321, U01 AI095532 and the Nebraska Tobacco Settlement Biomedical Research Program (LB692 and LB595). The project was also supported by Grant Number G20RR024001 from the National Center for Research Resources. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
          Categories
          Research Article
          Biology
          Immunology
          Immunity
          Innate Immunity
          Immune Response
          Microbiology
          Immunity
          Innate Immunity
          Host-Pathogen Interaction
          Parasitology
          Protozoology
          Molecular Cell Biology
          Cellular Types
          Epithelial Cells
          Gene Expression
          Histone Modification
          RNA interference
          Nucleic Acids
          RNA
          Signal Transduction
          Signaling Pathways
          Medicine
          Infectious Diseases
          Parasitic Diseases
          Cryptosporidiosis
          Gastrointestinal Infections

          Uncategorized
          Uncategorized

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