title: RNase-L deficiency exacerbates experimental colitis and colitis-associated cancer.
abstract: BACKGROUND
  The endoribonuclease RNase-L is a type-I interferon (IFN)-regulated component of the innate immune response that functions in antiviral, antibacterial, and antiproliferative activities. RNase-L produces RNA agonists of RIG-I-like receptors, sensors of cytosolic pathogen-associated RNAs that induce cytokines including IFN-β. IFN-β and RIG-I-like receptors signaling mediate protective responses against experimental colitis and colitis-associated cancer and contribute to gastrointestinal homeostasis. Therefore, we investigated a role for RNase-L in murine colitis and colitis-associated cancer and its association with RIG-I-like receptors signaling in response to bacterial RNA.
  
  
  METHODS
  Colitis was induced in wild type-deficient and RNase-L-deficient mice (RNase-L⁻/⁻) by administration of dextran sulfate sodium (DSS). Colitis-associated cancer was induced by DSS and azoxymethane (AOM). Histological analysis and immunohistochemistry were performed on colon tissue to analyze immune cell infiltration and tissue damage after induction of colitis. Expression of cytokines was measured by quantitative real-time-PCR and ELISA.
  
  
  RESULTS
  DSS-treated RNase-L⁻/⁻ mice exhibited a significantly higher clinical score, delayed leukocyte infiltration, reduced expression of IFN-β, tumor necrosis factor α, interleukin-1β, and interleukin-18 at early times post-DSS exposure, and increased mortality as compared with wild-type mice. DSS/AOM-treated RNase-L⁻/⁻ mice displayed an increased tumor burden. Bacterial RNA triggered IFN-β production in an RNase-L-dependent manner and provided a potential mechanism by which RNase-L contributes to the gastrointestinal immune response to microbiota and protects against experimental colitis and colitis-associated cancer.
  
  
  CONCLUSIONS
  RNase-L promotes the innate immune response to intestinal damage and ameliorates murine colitis and colitis-associated cancer. The RNase-L-dependent production of IFN-β stimulated by bacterial RNA may be a mechanism to protect against gastrointestinal inflammatory disease.
authors.affiliation: Graduate Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Tiha M
authors.initials: TM
authors.lastname: Long
authors.forename: Arindam
authors.initials: A
authors.lastname: Chakrabarti
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Ezelle
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Brennan-Laun
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Raufman
authors.forename: Irina
authors.initials: I
authors.lastname: Polyakova
authors.forename: Robert H
authors.initials: RH
authors.lastname: Silverman
authors.forename: Bret A
authors.initials: BA
authors.lastname: Hassel
mesh_terms: D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D003092:Colitis / Q000139:chemically induced / Q000150:complications*; D003110:Colonic Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D004722:Endoribonucleases / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000276:immunology*; D007124:Immunoenzyme Techniques; D007370:Interferon Type I / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D002273:Carcinogens; D016207:Cytokines; D007370:Interferon Type I; D012333:RNA, Messenger; D016264:Dextran Sulfate; D009195:Peroxidase; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; D001397:Azoxymethane