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Endocrinology Vol. 138, No. 7 2747-2753
Copyright © 1997 by The Endocrine Society

ARTICLES

Interferon-{gamma}-Induced Interferon Regulatory Factor-1 (IRF-1) Expression in Rodent and Human Islet Cells Precedes Nitric Oxide Production1

Malin Flodström and Décio L. Eizirik

Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden (M.F., D.L.E.) and Department of Metabolism and Endocrinology, Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium (D.L.E.)

Address all correspondence and requests for reprints to: Malin Flodström, Department of Medical Cell Biology, Uppsala University, Box 571, S-751 23 Uppsala, Sweden. E-mail: malin.flodstrom{at}medcellbiol.uu.se

The radical nitric oxide (NO) may be a mediator of ß-cell damage in IDDM. The cytokines IFN-{gamma} and IL-1ß are required for expression of the enzyme nitric oxide synthase (iNOS), and NO production by human pancreatic islets. In this study, possible mechanisms by which IFN-{gamma} participates in iNOS messenger RNA (mRNA) expression were evaluated in both rodent and human islets cells. Addition of IFN-{gamma}, before or after arrest of IL-1ß-induced iNOS gene transcription by actinomycin D, did not prolong iNOS mRNA half life in the rat insulin-producing cell line RINm5F (RIN cells). IFN-{gamma} also failed to modify IL-1ß-induced activation of the transcription factor {kappa}B (NF-{kappa}B) in RIN cells, as determined by electrophoretic mobility shift assay. However, IFN-{gamma} induced an early (30 min–1 h) increase in interferon regulatory factor-1 (IRF-1) mRNA expression and a later (2 h) 19-fold increase in RIN cell nuclear IRF-1 protein content, an effect further potentiated by IL-1ß. The total cellular content of IRF-1 protein increased by 30- to 50-fold in human islets exposed for 2–8h to IFN-{gamma} or IFN-{gamma} + IL-1ß. IL-1ß alone induced a marginal and transient increase in IRF-1. It has been previously reported that nicotinamide prevents IL-1ß-induced IRF-1 expression in rat pancreatic islets. However, nicotinamide (20 mM) presently failed to prevent IL-1ß + IFN-{gamma}-induced IRF-1 protein expression in human pancreatic islets. In conclusion, the effects of IFN-{gamma} on iNOS expression can neither be explained by iNOS mRNA stabilization nor increased NF-{kappa}B activation. However, IFN-{gamma} induces an early increase in cellular IRF-1 content, and this may contribute to increased iNOS mRNA expression.




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