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J. Biol. Chem., Vol. 278, Issue 25, 23055-23065, June 20, 2003

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Cytokine-mediated Down-regulation of the Transcription Factor cAMP-response Element-binding Protein in Pancreatic -Cells^*

Purevsuren Jambal  , Sara Masterson  , Albina Nesterova  , Ron Bouchard  , Barbara Bergman ¶, John C. Hutton ¶, Linda M. Boxer ||, Jane E.-B. Reusch   and Subbiah Pugazhenthi   **

From the Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262, the Section of Endocrinology, Veterans Affairs Medical Center, Denver, Colorado 80220, and the ^¶Barbara Davis Center for Childhood Diabetes, Denver, Colorado 80220, and the ^||Department of Medicine, Stanford University School of Medicine, Stanford, California 94305

Cytokines are known to induce apoptosis of pancreatic -cells. Impaired expression of the anti-apoptotic gene bcl-2 is one of the mechanisms involved. In this study, we identified a defect involving transcription factor cAMP-response element-binding protein (CREB) in the expression of bcl-2. Exposure of mouse pancreatic -cell line, MIN6 cells, to cytokines (interleukin-1, tumor necrosis factor-, and interferon-) led to a significant (p < 0.01) decrease in Bcl-2 protein and mRNA levels. Cytokines decreased (56%) the activity of the bcl-2 promoter that contains a cAMP-response element (CRE) site. Similar decreases were seen with a luciferase reporter gene driven by tandem repeats of CRE and a CREB-specific Gal4-luciferase reporter, suggesting a defect at the level of CREB. The active phospho form (serine 133) of CREB diminished significantly (p < 0.01) in cells exposed to cytokines. Examination of signaling pathways upstream of CREB revealed a reduction in the active form of Akt. Cytokine-induced decrease of bcl-2 promoter activity was partially restored when cells were cotransfected with a constitutively active form of Akt. Several end points of cytokine action including decreases in phospho-CREB, phospho-Akt, and BCl-2 levels and activation of caspase-9 were observed in isolated mouse islets. Overexpression of wild-type CREB in MIN6 cells by plasmid transfection and adenoviral infection led to protection against cytokine-induced apoptosis. Adenoviral transfer of dominant-negative forms of CREB, on the other hand, resulted in activation of caspase-9 and exaggeration of cytokine-induced -cell apoptosis. Together, these results point to CREB as a novel target for strategies aimed at improving the survival of -cells.

Received for publication, December 6, 2002 , and in revised form, March 25, 2003.

^* This work was supported by an American Diabetes Association Innovation award (to S. P.), by a grant from Veterans Affairs MERIT Review (to J. E.-B. R.), and by Diabetes and Endocrinology Research Center Grant DK 57516-03 at Barbara Davis Center (to J. C. H.). 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.

^** To whom correspondence should be addressed: Division of Endocrinology, Dept. of Medicine, 4200 E. Ninth Ave., Denver, CO 80262. Tel.: 303-399-8020 (ext. 3004); Fax: 303-393-5271; E-mail: subbiah.pugazhenthi{at}uchsc.edu.

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