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* Department of Medicine, and
Department of Pediatrics, University of California at San Diego, La Jolla, CA 92093
Intestinal epithelial cells (IECs) are a first line of defense against microbial pathogens that enter the host through the intestinal tract. Moreover, viral pathogens that infect the host via the intestinal epithelium are an important cause of morbidity and mortality. However, the mechanisms by which viral pathogens activate antiviral defense mechanisms in IECs are largely unknown. The synthetic dsRNA analog polyinosinic-polycytidylic acid and infection with live virus were used to probe the molecules that are activated and the mechanisms of signaling in virus-infected human IECs. Polyinosinic-polycytidylic acid activated IFN regulatory factor 3 dimerization and phosphorylation, increased activity of the IFN-stimulated response element, induced a significant increase in IFN-
mRNA transcripts and IFN- secretion, and up-regulated the expression of IFN-regulated genes in IECs. Those responses were dependent upon activation of the dsRNA binding protein retinoic acid inducible gene I (RIG-I) and the RIG-I interacting protein IFN promoter stimulator-1, but not on dsRNA-activated protein kinase or TLR3, which also were expressed by IECs. Virus replication and virus-induced cell death increased in IECs in which RIG-I was silenced, consistent with the importance of the RIG-I signaling pathway in IEC antiviral innate immune defense mechanisms.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants DK58960 and DK35108, a grant from the William K. Warren Foundation, a fellowship from the Sankyo Foundation of Life Science (to Y.H.), and a fellowship from the Instituto de Salud Carlos III (to L.M.).
2 Address correspondence and reprint requests to Dr. Martin F. Kagnoff, Laboratory of Mucosal Immunology, Department of Medicine, Mail Code 0623-D, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093. E-mail address: mkagnoff{at}ucsd.edu
3 Abbreviations used in this paper: IEC, intestinal epithelial cell; 2-AP, 2-aminopurine; CARD, caspase activation and recruitment domain; DN, dominant negative; IPS-1, interferon promoter stimulator-1; IRF3, interferon regulatory factor 3; ISRE, IFN-stimulated response element; LF, lipofectamine; MDA5, myeloma differentiation associated gene 5; MOI, multiplicity of infection; pIC-L, poly(I:C) in PBS containing LF; pIC-P, poly(I:C) in PBS; PKR, dsRNA-activated protein kinase; poly(I:C), polyinosinic-polycytidylic acid; RIG-I, retinoic acid inducible gene I; siRNA, small interfering RNA; TRIF, Toll/IL-1R domain-containing adaptor inducing IFN-; VSV, vesicular stomatitis virus.
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