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Nuclear Factor-B Translocation Mediates Double-Stranded Ribonucleic Acid-Induced NIT-1 ß-Cell Apoptosis and Up-Regulates Caspase-12 and Tumor Necrosis Factor Receptor-Associated Ligand (TRAIL)

Department of Pathology (M.A.R., J.K.C.), University of British Columbia, and British Columbia Research Institute for Children’s and Women’s Health (M.A.R., L.M., E.P., J.K.C.), Vancouver, British Columbia, Canada V5Z 4H4

Address all correspondence and requests for reprints to: Janet K. Chantler, Ph.D., British Columbia Research Institute for Children’s and Women’s Health, Room 318, 950 West 28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4. E-mail: chantler{at}interchange.ubc.ca.

Abstract

The mechanism of induction of apoptosis by double-stranded RNA (dsRNA) is not fully characterized. The dsRNA is normally present in extremely low quantities in cells, but following infection with RNA viruses, large quantities of the dsRNA viral replicative intermediate may be produced triggering the antiviral response as well as cell death. In this report, transfection of polyinosinic-polycytidylic acid [poly(I:C)] into NIT 1 cells has been used as a model of intracellular dsRNA-induced ß-cell apoptosis. At 18 h post transfection, 45% of the cells were apoptotic as indicated by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) staining, and this was accompanied by an increase in nuclear factor B (NF-B) p50/p65 nuclear translocation and cleavage of caspases 3 and 8. The NF-B inhibitor peptide, SN50, significantly reduced caspase-3 activity and the percentage of TUNEL-positive cells, substantiating a role for NF-B in inducing intracellular dsRNA-mediated apoptosis. Concomitantly, RNA-dependent protein kinase activity was observed at 3 h post transfection along with phosphorylation and degradation of inhibitory B-. Expression of TRAIL (TNF-related apoptosis-inducing ligand), Fas, IL-15, and caspase-12 mRNAs was up-regulated in the presence of poly(I:C) but not when SN50 was also added. In contrast, there was no change detected in Fas, Fas-associated death domain, Bcl-2, Bcl-xl, Bax, p53, or XIAP(X-linked inhibitor of apoptosis protein) expression up to 12 h after poly(I:C) transfection. In addition, caspase-12 was cleaved, and phosphorylation of eukaryotic initiation factor 2 occurred, suggesting that an endoplasmic reticulum stress pathway was involved in addition to NF-B induction of an extrinsic pathway, possibly mediated by TNF-related apoptosis-inducing ligand.

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