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.
Article first published online 4 April 2013
*Graduate Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, Maryland;
†Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio;
‡Marlene and Stewart Greenebaum Cancer Center,
§Department of Microbiology and Immunology, and
‖Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, Maryland; and
¶Research Services, Baltimore Veteran's Administration Medical Center, Baltimore, Maryland.
Reprints: Bret A. Hassel, PhD, Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 West Baltimore Street, HSF1-380 Baltimore, MD 21201 (e-mail: firstname.lastname@example.org).
T. M. Long and A. Chakrabarti contributed equally to the study.
R. H. Silverman is a consultant and inventor on patents relating to RNase-L licensed to Alios BioPharma. B. A. Hassel is an inventor on patents relating to RNase-L licensed to AliosBiopharma. All other authors have no conflicts of interest to disclose.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (http://www.ibdjournal.org).
Supported by NIH, NCI grant CA044059 (to RHS), NCI grant CA120407 (to J-PR), NIAID grant AI077556 (to BAH), and a Marlene and Stewart Greenebaum Cancer Center Pilot Grant (to BAH).
Received October 18, 2012
Accepted October 30, 2012