MAPK kinase kinase-1 is essential for cytokine-induced c-Jun NH2-terminal kinase and nuclear factor-kappaB activation in human pancreatic islet cells
2008 (English)In: Diabetes, ISSN 0012-1797, Vol. 57, no 7, 1896-1904 p.Article in journal (Refereed) Published
OBJECTIVE: The transcription factor nuclear factor-kappaB (NF-kappaB) and the mitogen-activated protein kinases (MAPKs) c-Jun NH(2)-terminal kinase (JNK) 1/2 are known to play decisive roles in cytokine-induced damage of rodent beta-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 betaTC-6 cells, achieved by lipofection and cell sorting, and MEKK-1 downregulation in betaTC-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 kappaB (IkappaB) 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, IkappaB stability, and a less pronounced NF-kappaB translocation. betaTC-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-kappaB activation, and this event is necessary for iNOS expression and cell death.
Place, publisher, year, edition, pages
2008. Vol. 57, no 7, 1896-1904 p.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-99812DOI: 10.2337/db07-1670ISI: 000257420000019PubMedID: 18420486OAI: oai:DiVA.org:uu-99812DiVA: diva2:208788