Glucose potentiates interleukin-1 beta (IL-1 beta)-induced p38 mitogen-activated protein kinase activity in rat pancreatic islets of Langerhans.
The cytokine interleukin-1 beta (IL-1 beta) is cytotoxic to rat pancreatic beta-cells and has been implicated in the pathogenesis of insulin-dependent diabetes mellitus. IL-1 beta causes expression of inducible nitric oxide synthase (iNOS) and production of nitric oxide (NO). NO may be the mediator of the cytotoxic effect of IL-1 beta in rat islets and beta-cell lines. Glucose has been shown to modulate the effects of IL-1 beta on accumulated insulin release and potentiate NO production in rat islets, but the biochemical mechanism is unknown. IL-1 beta activates the mitogen-activated protein kinases (MAPK) extracellular signal-regulated kinase 1 and 2 (ERK1/2), p38 and c-jun NH2-terminal kinase (JNK) in rat islets and beta-cells. Glucose may modulate MAPK activity although contrasting data have been published. The aim of this study was to investigate whether glucose potentiated IL-1 beta-induced p38 and ERK1/2 activity in rat islets. It was shown that glucose alone increased the phosphorylation of the MAPK substrates Elk-1 and activating transcription factor 2 (ATF2). D-glucose potentiated the p38 activity induced by a low concentration of IL-1 beta, whereas no effect was seen at high concentrations of IL-1 beta. Inhibition of p38 activity prevented IL-1 beta-induced nitrite production in the presence of D-glucose. We conclude that IL-1 beta-induced NO production in the presence of glucose is signalled by the p38 pathway.
Sprinkel
A M
AM
Steno Diabetes Center, 2 Niels Steensens vej, DK-2820 Gentofte, Denmark.
Andersen
N A
NA
Mandrup-Poulsen
T
T
D051698:Activating Transcription Factor 2; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins; D005947:Glucose / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000201:enzymology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009573:Nitrites / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013379:Substrate Specificity; D014157:Transcription Factors / Q000378:metabolism; D050807:ets-Domain Protein Elk-1; D048051:p38 Mitogen-Activated Protein Kinases
D051698:Activating Transcription Factor 2; C497107:Atf2 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; C494114:Elk1 protein, rat; D007375:Interleukin-1; D009573:Nitrites; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose