Nitric oxide contributes to cytokine-induced apoptosis in pancreatic beta cells via potentiation of JNK activity and inhibition of Akt

Autor: Stellan Sandler, Thomas Mandrup-Poulsen, Giatgen A. Spinas, Richard Züllig, Ake Andersson, Roger Lehmann, Joachim Størling, Nils Billestrup, J. Binzer, M. Tonnesen
Rok vydání: 2005
Předmět:
medicine.medical_specialty
MAP Kinase Kinase 4
Endocrinology
Diabetes and Metabolism
p38 mitogen-activated protein kinases
medicine.medical_treatment
Blotting
Western
Nitric Oxide Synthase Type II
Apoptosis
Cell Separation
Biology
S-Nitroso-N-Acetylpenicillamine
Nitric Oxide
p38 Mitogen-Activated Protein Kinases
Nitric oxide
chemistry.chemical_compound
Mice
Internal medicine
Insulin-Secreting Cells
Insulin Secretion
Internal Medicine
medicine
Animals
Humans
Insulin
Nitric Oxide Donors
Enzyme Inhibitors
Protein kinase B
Cells
Cultured
Dose-Response Relationship
Drug
Kinase
Cell biology
Enzyme Activation
Oncogene Protein v-akt
Endocrinology
Cytokine
NG-Nitroarginine Methyl Ester
chemistry
Mitogen-activated protein kinase
biology.protein
Cytokines
Signal transduction
Beta cell
Mitogen-Activated Protein Kinases
Signal Transduction
Zdroj: Diabetologia. 48(10)
ISSN: 0012-186X
Popis: Pro-inflammatory cytokines cause beta cell secretory dysfunction and apoptosis--a process implicated in the pathogenesis of type 1 diabetes. Cytokines induce the expression of inducible nitric oxide (NO) synthase (iNOS) leading to NO production. NO contributes to cytokine-induced apoptosis, but the underlying mechanisms are unclear. The aim of this study was to investigate whether NO modulates signalling via mitogen-activated protein kinases (MAPKs) and Akt.MAPK activities in INS-1 cells and isolated islets were determined by immunoblotting and in vitro kinase assay. Apoptosis was determined by ELISA measurement of histone-DNA complexes present in cytoplasm.Apoptosis in INS-1 cells induced by IL-1beta plus IFNgamma was dependent on NO production as demonstrated by the use of the NOS blocker NG-methyl-L-arginine. Accordingly, an NO donor (S-nitroso-N-acetyl-D, L-penicillamine, SNAP) dose-dependently caused apoptosis in INS-1 cells. SNAP activated c-Jun N-terminal kinase (JNK) and p38 MAPK, but suppressed the activity of extracellular signal-regulated kinase MAPK. In rat islets, NOS inhibition decreased JNK and p38 activities induced by a 6-h exposure to IL-1beta. Likewise, IL-1beta-induced JNK and p38 activities were lower in iNOS(-/-) mouse islets than in wild-type islets. In human islets, SNAP potentiated IL-1beta-induced JNK activation. The constitutive level of active, Ser473-phosphorylated Akt in INS-1 cells was suppressed by SNAP. IGF-I activated Akt and protected against SNAP-induced apoptosis. The anti-apoptotic effect of IGF-I was not associated with reduced JNK activation.We suggest that NO contributes to cytokine-induced apoptosis via potentiation of JNK activity and suppression of Akt.
Databáze: OpenAIRE
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