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In the current study, we present multiple lines of evidence supporting the conclusion that cytokine-induced killing of rat \u03b2-cells occurs predominantly by a nonapoptotic mechanism, including the following: 1) A rat \u03b2-cell line selected for resistance to cytokine-induced cytotoxicity (833\/15) is equally sensitive to killing by the apoptosis-inducing agents camptothecin and etoposide as a cytokine-sensitive cell line (832\/13). 2) Overexpression of a constitutively active form of the antiapoptotic protein kinase Akt1 in 832\/13 cells provides significant protection against cell killing induced by camptothecin and etoposide but no protection against cytokine-mediated damage. 3) Small interfering RNA\u2013mediated suppression of the proapoptotic protein Bax enhances viability of 832\/13 cells upon exposure to the known apoptosis-inducing drugs but not the inflammatory cytokines. 4) Exposure of primary rat islets or 832\/13 cells to the inflammatory cytokines causes cell death as evidenced by the release of adenylate kinase activity into the cell medium, with no attendant increase in caspase 3 activation or annexin V staining. In contrast, camptothecin- and etoposide-induced killing is associated with robust increases in caspase 3 activation and annexin V staining. 5) Camptothecin increases cellular ATP levels, whereas inflammatory cytokines lower ATP levels in both \u03b2-cell lines and primary islets. We conclude that proinflammatory cytokines cause \u03b2-cell cytotoxicity primarily through a nonapoptotic mechanism linked to a decline in ATP levels.<\/jats:p>","DOI":"10.2337\/db05-1000","type":"journal-article","created":{"date-parts":[[2006,5,10]],"date-time":"2006-05-10T22:48:46Z","timestamp":1147301326000},"page":"1398-1406","update-policy":"http:\/\/dx.doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":62,"title":["Pro- and Antiapoptotic Proteins Regulate Apoptosis but Do Not Protect Against Cytokine-Mediated Cytotoxicity in Rat Islets and \u03b2-Cell Lines"],"prefix":"10.2337","volume":"55","author":[{"given":"J. Jason","family":"Collier","sequence":"first","affiliation":[{"name":"Sarah W. Stedman Nutrition and Metabolism Center and the Department of Pharmacology and Cancer Biology, Duke University Medical Center Durham, Norh Carolina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick T.","family":"Fueger","sequence":"additional","affiliation":[{"name":"Sarah W. Stedman Nutrition and Metabolism Center and the Department of Pharmacology and Cancer Biology, Duke University Medical Center Durham, Norh Carolina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans E.","family":"Hohmeier","sequence":"additional","affiliation":[{"name":"Sarah W. 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