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PMID: 16132952 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Diabetologia ·Vol. 48 ·No. 10 ·2005-10-00 ·Pages 2039-50

Størling J, Binzer J, Andersson AK, Züllig RA, Tonnesen M, Lehmann R, Spinas GA, Sandler S, Billestrup N, Mandrup-Poulsen T

Abstract

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.

MeSH Terms
Animals Apoptosis/drug effects Blotting, Western Cell Separation Cells, Cultured Cytokines/pharmacology Dose-Response Relationship, Drug Enzyme Activation/drug effects Enzyme Inhibitors/pharmacology Humans Insulin/metabolism Insulin Secretion Insulin-Secreting Cells/drug effects,metabolism MAP Kinase Kinase 4/genetics Mice Mitogen-Activated Protein Kinases/metabolism NG-Nitroarginine Methyl Ester/pharmacology Nitric Oxide/physiology Nitric Oxide Donors/pharmacology Nitric Oxide Synthase Type II/antagonists & inhibitors Oncogene Protein v-akt/genetics S-Nitroso-N-Acetylpenicillamine/pharmacology Signal Transduction p38 Mitogen-Activated Protein Kinases/metabolism
Chemicals
Cytokines Enzyme Inhibitors Insulin Nitric Oxide Donors Nitric Oxide S-Nitroso-N-Acetylpenicillamine Nitric Oxide Synthase Type II Oncogene Protein v-akt Mitogen-Activated Protein Kinases p38 Mitogen-Activated Protein Kinases MAP Kinase Kinase 4 NG-Nitroarginine Methyl Ester
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Størling J
Laboratory for Beta Cell Biology, Steno Diabetes Center, Gentofte, Denmark. [email protected]
Binzer J
Andersson A K
Züllig R A
Tonnesen M
Lehmann R
Spinas G A
Sandler S
Billestrup N
Mandrup-Poulsen T
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Article Info
Journal
Diabetologia
Abbr.
Diabetologia
ISSN
0012-186X
DOI
10.1007/s00125-005-1912-2
Email
[email protected]
Published
2005-10-00
Epub
2005-00-25
Pages
2039-50
Language
English
Region
Germany
NLM ID
0006777
Subset
IM
External Links
PubMed source DOI: 10.1007/s00125-005-1912-2 View journal details
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