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Transforming Growth Factor-β-Activated Protein Kinase 1-Binding Protein (TAB)-1, But Not TAB1β, Mediates Cytokine-Induced p38 Mitogen-Activated Protein Kinase Phosphorylation and Cell Death in Insulin-Producing Cells

Department of Medical Cell Biology (N.M., G.M.R., N.W.), Uppsala University, S-75123 Uppsala, Sweden; and Department of Biochemistry (J.W.M.), Stanford University School of Medicine, Stanford, California 94305

Address all correspondence and requests for reprints to: Nils Welsh, Department of Medical Cell Biology, Husargatan 3, S-75123 Uppsala, Sweden. E-mail: nils.welsh{at}mcb.uu.se.

Previous studies have indicated that the p38 MAPK participates in signaling events that lead to the death of the insulin-producing β-cell. The aim of the present study was to elucidate the role of the TGF-β-activated protein kinase 1-binding protein 1 (TAB1) in the cytokine-induced activation of p38. Levels of TAB1 mRNA and protein were analyzed by real-time PCR and immunoblotting, and TAB1 expression in mouse and human islet cells was down-regulated using lipofection of diced-small interfering RNA. TAB1 overexpression in β-TC6 cells was achieved by transient transfections followed by fluorescence activated cell sorting. Phosphorylation of p38, c-Jun N-terminal kinase, and ERK was assessed by immunoblotting, and viability was determined using vital staining with bisbenzimide and propidium iodide. We observed that TAB1 is expressed in insulin-producing cells. Cytokine (IL-1β + interferon-)-stimulated p38 phosphorylation was significantly increased by TAB1 overexpression, but not TAB1β overexpression, in β-TC6 cells. The TAB1-augmented p38 phosphorylation was paralleled by an increased cell death rate. Treatment of islet cells with diced-small interfering RNA specific for TAB1, but not for TGF-β-activated kinase 1, resulted in lowered cytokine-induced p38 phosphorylation and protection against cell death. The cytokine-induced phosphorylation of c-Jun N-terminal kinase and ERK was not affected by changes in TAB1 levels. Finally, TAB1 phosphorylation was decreased by the p38 inhibitor SB203580. We conclude that TAB1, but not TAB1β, plays an important role in the activation of p38 in insulin-producing cells and therefore also in cytokine-induced β-cell death.

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