Previous studies have indicated that the p38 MAPK participates in signaling events that lead to the death of the insulin-producing -cell. The aim of the present study was to elucidate the role of the transforming growth factor--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-siRNA. TAB1 over-expression in -TC6 cells was achieved by transient transfections followed by fluorescence activated cell sorting. Phosphorylation of p38, JNK 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-1 + IFN-)-stimulated p38 phosphorylation was significantly increased by TAB1 overexpression, but not by TAB1 overexpression, in -TC6 cells. The TAB1-augmented p38 phosphorylation was paralleled by an increased cell death rate. Treatment of islet cells with diced-siRNA specific for TAB1, but not for TAK1, resulted in lowered cytokine-induced p38 phosphorylation and protection against cell death. The cytokine-induced phosphorylation of JNK 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 TAB1, plays an important role in the activation of p38 in insulin-producing cells and therefore also in cytokine-induced -cell death.