Faculty Collaboration Database

Nitric oxide mediates IL-1 beta-induced islet dysfunction and destruction: prevention by dexamethasone. Autoimmunity 1993;15(2):145-53

Date

01/01/1993

Pubmed ID

7692996

DOI

10.3109/08916939309043889

Scopus ID

2-s2.0-0027301777 (requires institutional sign-in at Scopus site)   84 Citations

Abstract

Nitric oxide has recently been implicated as a cellular molecule that mediates interleukin-1 beta (IL-1 beta)-induced inhibition of glucose-stimulated insulin secretion by islets of Langerhans. In this study evidence is presented which demonstrates that islets contain both the cytokine inducible and the constitutive isoforms of nitric oxide synthase as determined by NADPH diaphorase staining and immunohistochemical localization. Untreated islets contain NADPH diaphorase activity, and the intensity of NADPH diaphorase staining is dramatically increased after culture for 18 hrs with IL-1 beta. Both control and IL-1 beta-induced NADPH diaphorase staining of islets is inhibited by the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (NMMA). Importantly, approximately 60-70% of islet cells stained positive for NADPH diaphorase (under both IL-1 beta treated and control conditions), suggesting that a subset of islet cells contain nitric oxide synthase. The beta-cell appears to be the endocrine cell type which contains constitutive nitric oxide synthase as demonstrated by immunohistochemical co-localization of constitutive nitric oxide synthase and insulin. IL-1 beta is believed to stimulate the expression of cytokine inducible nitric oxide synthase because the synthetic glucocorticoid, dexamethasone, prevents IL-1 beta induced inhibition of glucose stimulated insulin secretion and cGMP accumulation by islets. Both dexamethasone, and the nitric oxide synthase inhibitors NMMA and aminoguanidine also prevent IL-1 beta induced islet degeneration. These results indicate that nitric oxide produced by the inducible isoform of nitric oxide synthase mediates cytokine induced islet dysfunction and destruction, and that the beta-cell is the islet endocrine cellular source of constitutive nitric oxide synthase.

Author List

Corbett JA, Wang JL, Misko TP, Zhao W, Hickey WF, McDaniel ML

Author

John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amino Acid Oxidoreductases
Animals
Arginine
Cyclic GMP
Dexamethasone
Guanidines
Insulin
Interleukin-1
Islets of Langerhans
Male
NADPH Dehydrogenase
Nitric Oxide
Nitric Oxide Synthase
Rats
Rats, Sprague-Dawley
omega-N-Methylarginine