Nitric Oxide Is a Mediator of Antiproliferative Effects Induced by Proinflammatory Cytokines on Pancreatic Beta Cells

Author:

Quintana-Lopez Laura1,Blandino-Rosano Manuel1,Perez-Arana Gonzalo1,Cebada-Aleu Alberto1ORCID,Lechuga-Sancho Alfonso2,Aguilar-Diosdado Manuel3,Segundo Carmen34ORCID

Affiliation:

1. Investigation Unit, Puerta del Mar Hospital, Cadiz, Spain

2. Pediatric Endocrinology Unit of Paediatric Service, Puerta del Mar Hospital, Cadiz, Spain

3. Endocrinology and Nutrition Service, Puerta del Mar Hospital, 11009 Cadiz, Spain

4. “Salus Infirmorum” Faculty of Nursing, Cadiz University, Spain

Abstract

Nitric oxide (NO) is involved in several biological processes. In type 1 diabetes mellitus (T1DM), proinflammatory cytokines activate an inducible isoform of NOS (iNOS) inβcells, thus increasing NO levels and inducing apoptosis. The aim of the current study is to determine the role of NO (1) in the antiproliferative effect of proinflammatory cytokines IL-1β, IFN-γ, and TNF-αon cultured isletβcells and (2) during the insulitis stage prior to diabetes onset using the Biobreeding (BB) rat strain as T1DM model. Our results indicate that NO donors exert an antiproliferative effect onβcell obtained from cultured pancreatic islets, similar to that induced by proinflammatory cytokines. This cytokine-induced antiproliferative effect can be reversed by L-NMMA, a general NOS inhibitor, and is independent of guanylate cyclase pathway. Assays using NOS isoform specific inhibitors suggest that the NO implicated in the antiproliferative effect of proinflammatory cytokines is produced by inducible NOS, although not in an exclusive way. In BB rats, early treatment with L-NMMA improves the initial stage of insulitis. We conclude that NO is an important mediator of antiproliferative effect induced by proinflammatory cytokines on culturedβcell and is implicated inβ-cell proliferation impairment observed early from initial stage of insulitis.

Funder

Spanish Ministry of Health

Publisher

Hindawi Limited

Subject

Cell Biology,Immunology

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