Aminoguanidine downregulates expression of cytokine-induced Fas and inducible nitric oxide synthase but not cytokine-enhanced surface antigens of rat islet cells

• Published in: Biochemical pharmacology 2003-12, Vol.66 (12), p.2437-2448
• Main Authors: Kuttler, Beate, Steveling, Antje, Klöting, Nora, Morgenstern, Olaf, Wanka, Heike
• Format: Article
• Language: English
• Subjects: Aminoguanidine; Animals; Antigens, Surface - metabolism; Biological and medical sciences; Cytokines - pharmacology; Down-Regulation; Enzyme Inhibitors - pharmacology; Fas; fas Receptor - biosynthesis; Gene Expression Regulation - drug effects; Guanidines - pharmacology; ICAM-1; iNOS; Insulin - metabolism; Islets of Langerhans - drug effects; Islets of Langerhans - enzymology; Islets of Langerhans - metabolism; Medical sciences; MHC antigens; Nitric Oxide - metabolism; Nitric Oxide Synthase - biosynthesis; Nitric Oxide Synthase Type II; Pharmacology. Drug treatments; Rats; Rats, Inbred Lew; β-Cell destruction
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2003.09.002

Autoimmune β-cell destruction occurs directly by cell-mediated cytotoxicity or indirectly by cytokines released from infiltrating lymphocytes. Cytokines (IL-1β/IFN-γ) modify or induce expression of MHC antigens and ICAM-1 on β-cells which can lead to an improved binding of T-lymphocytes to β-cells and finally to an enhanced cell-mediated cytotoxicity. Cytokines also induce Fas-expression and inducible nitric oxide synthase (iNOS) causing generation of nitric oxide (NO) which is toxic for β-cells. The iNOS inhibitor aminoguanidine (AG) delays diabetes onset, but does not reduce diabetes incidence. We wanted to know whether AG inhibits cytokine-induced expression of Fas, MHC antigens and ICAM-1 on β-cells of LEW.1W and BB/OK rat islets after culture with IL-1β/IFN-γ. NO was completely inhibited by 5.0 mmol/L AG while 0.5 mmol/L had no inhibitory effect. AG downregulated Fas-expression on the surface of β-cells. Cytokine-induced/enhanced expression of MHC class-II and ICAM-1 was not affected by any AG concentration. AG syngergistically increased cytokine-induced enhancement of MHC class-I antigen density. AG possibly blocks the indirect pathway of β-cell damage in vivo due to inhibition of Fas and iNOS and improves direct cell-mediated cytotoxicity due to drastic increased MHC class-I expression. Inhibition of only one pathway of β-cell destruction is not sufficient to prevent diabetes.