Faculty Collaboration Database

Interleukin-1 plus gamma-interferon-induced pancreatic beta-cell dysfunction is mediated by beta-cell nitric oxide production. Diabetes 2002 Feb;51(2):311-6

Date

01/29/2002

Pubmed ID

11812737

DOI

10.2337/diabetes.51.2.311

Scopus ID

2-s2.0-0036068246 (requires institutional sign-in at Scopus site)   159 Citations

Abstract

Cytokines have been implicated in pancreatic beta-cell destruction leading to type 1 diabetes. In vitro, a combination of gamma-interferon (IFN-gamma) and interleukin-1 (IL-1) stimulate inducible nitric oxide synthase (iNOS) expression in islets, and the resulting increased production of nitric oxide (NO) causes islet cell destruction. Islets contain macrophages, ductal cells, and endothelial cells that, when activated, may mediate islet cell damage by producing either NO themselves or cytokines that then stimulate NO production by beta-cells. The aim of this study was to determine whether beta-cell damage mediated by cytokine-induced NO production is dependent on beta-cell production of NO, or whether NO produced by other cells in the islet is capable of destroying beta-cells. To address this aim, we used transgenic mice expressing a dominant-negative IFN-gamma receptor in beta-cells (RIP-Delta(gamma)R). RIP-Delta(gamma)R islets are resistant to IL-1 + IFN-gamma-induced inhibition of insulin secretion and DNA damage, indicating that beta-cell IFN-gamma responsiveness is required for IL-1 + IFN-gamma-mediated beta-cell damage. Although islets isolated from RIP-Delta(gamma)R mice are resistant to functional damage, these islets produce NO in response to IL-1 + IFN-gamma, but at a lower concentration than that produced by wild-type islets. beta-Cells appear to be the primary cellular source of IL-1 + IFN-gamma-induced iNOS expression in wild-type islets. In contrast, IL-1 + IFN-gamma fail to stimulate iNOS expression by insulin-expressing cells in islets isolated from RIP-DeltagammaR mice. IL-1 + IFN-gamma-induced expression of iNOS was detected in non-beta-cells in both wild-type and RIP-DeltagammaR islets. These findings support the hypothesis that NO must be produced by beta-cells to induce damage.

Author List

Thomas HE, Darwiche R, Corbett JA, Kay TW

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

Animals
Cell Death
Drug Combinations
Genes, Dominant
Glucose
In Vitro Techniques
Insulin
Interferon-gamma
Interleukin-1
Islets of Langerhans
Mice
Mice, Inbred NOD
Mice, Inbred Strains
Mice, Transgenic
Nitric Oxide
Nitric Oxide Synthase
Nitric Oxide Synthase Type II
Receptors, Interferon