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MAPK Kinase Kinase-1 Is Essential for Cytokine-Induced c-Jun NH₂-Terminal Kinase and Nuclear Factor-B Activation in Human Pancreatic Islet Cells

¹ Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
² Department of Biochemistry, Stanford University School of Medicine, Stanford, California

Corresponding author: Nils Welsh, nils.welsh{at}mcb.uu.se

OBJECTIVE—The transcription factor nuclear factor-B (NF-B) and the mitogen-activated protein kinases (MAPKs) c-Jun NH₂-terminal kinase (JNK) 1/2 are known to play decisive roles in cytokine-induced damage of rodent β-cells. The upstream events by which these factors are activated in response to cytokines are, however, uncharacterized. The aim of the present investigation was to elucidate a putative role of the MAPK kinase kinase-1 (MEKK-1) in cytokine-induced signaling.

RESEARCH DESIGN AND METHODS—To establish a functional role of MEKK-1, the effects of transient MEKK-1 overexpression in βTC-6 cells, achieved by lipofection and cell sorting, and MEKK-1 downregulation in βTC-6 cells and human islet cells, achieved by diced–small interfering RNA treatment, were studied.

RESULTS—We observed that overexpression of wild-type MEKK-1, but not of a kinase dead MEKK-1 mutant, resulted in potentiation of cytokine-induced JNK activation, inhibitor of B (IB) degradation, and cell death. Downregulation of MEKK-1 in human islet cells provoked opposite effects, i.e., attenuation of cytokine-induced JNK and MKK4 activation, IB stability, and a less pronounced NF-B translocation. βTC-6 cells with a downregulated MEKK-1 expression displayed also a weaker cytokine-induced iNOS expression and lower cell death rates. Also primary mouse islet cells with downregulated MEKK-1 expression were protected against cytokine-induced cell death.

CONCLUSIONS—MEKK-1 mediates cytokine-induced JNK- and NF-B activation, and this event is necessary for iNOS expression and cell death.

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