uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Regulation of cytokine-induced nitric oxide production in insulin-producing cells
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
1998 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cytokine-induced expression of the inducible form of nitric oxide synthase (iNOS) and production of nitric oxide (NO) may contribute to pancreatic β-cell damage during the development of type 1 diabetes. iNOS catalyses the conversion of arginine into citrulline and NO, a reaction regulated by the amount of expressed iNOS enzyme and by the cellular availability of arginine. Activation of the transcriptional regulator nuclear factor κB (NF-κB) is required for the expression of iNOS in diverse rodent cells. Activation of NF-κB was presently observed to be necessary but not sufficient for the induction of iNOS by cytokines (IL-1β + IFN-γ + TNF-α) in human islets. This suggests that other transcription factors may play a role in this process. IFN-γ alone or in combination with IL-1β induced the expression of the transcription factor interferon regulatory factor-l (IRF-1) both in rodent and human islets. IRF-1 is necessary for iNOS expression by murine macrophages and may therefore also contribute to the expression of iNOS in insulin-producing cells. Synthesis of NO by cytokine-exposed purified rat β-cells, rodent and human islets was found to depend on the presence of extracellular arginine or citrulline, with arginine levels similar to that observed in plasma (80-200 µM) limiting NO-production. Cytokine-stimulated purified rat β-cells and human and rat islets used citrulline as efficiently as arginine for NO-synthesis, suggesting an intracellular generation of arginine by a citrulline-NO cycle. In line with this hypothesis, IL-1β or IFN-γ + TNF-α enhanced mRNA expression and enzyme activity of argininosuccinate synthetase (AS), the rate-limiting enzyme in the citrulline-NO cycle, in insulin-producing cells. This was paralleled by the induction of iNOS mRNA. Moreover, IL-1β increased arginine accumulation by purified rat β-cells.

It is concluded that NF-κB, and possibly IRF-1, contribute to the expression of iNOS in cytokine-exposed insulin-producing rat β-cells and intact human and rat islets. Cytokines also increase the β-cell capacity to accumulate arginine and activate the citrulline-NO cycle. This adaptive response in cytokine-exposed insulin-producing cells may be of relevance to assure an adequate arginine supply for durable NO synthesis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 1998. , [4], 75 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 735
Keyword [en]
Cell biology, Diabetes, pancreatic islets, insulin-producing cells, cytokines, nitric oxide, inducible nitric oxide synthase, nuclear factor-kappaB, interferon regulatory factor-1, arginine, citrulline, argininosuccinate synthetase, insulin release
Keyword [sv]
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
URN: urn:nbn:se:uu:diva-132ISBN: 91-554-4120-3OAI: oai:DiVA.org:uu-132DiVA: diva2:160855
Public defence
1998-02-06, lecture hall B21, Uppsala Biomedical Centre, Uppsala University, Uppsala, 09:15
Available from: 1998-01-16 Created: 1998-01-16Bibliographically approved

Open Access in DiVA

No full text
Buy this publication >>

By organisation
Department of Medical Cell Biology
Cell and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Total: 196 hits
ReferencesLink to record
Permanent link

Direct link