Nitric oxide mediates cytokine-induced inhibition of insulin secretion by human islets of Langerhans. Proc Natl Acad Sci U S A 1993 Mar 01;90(5):1731-5
Date
03/01/1993Pubmed ID
8383325Pubmed Central ID
PMC45953DOI
10.1073/pnas.90.5.1731Scopus ID
2-s2.0-0027534895 (requires institutional sign-in at Scopus site) 429 CitationsAbstract
Cytokines have been implicated as immunological effector molecules that mediate beta cell destruction associated with insulin-dependent diabetes mellitus. In this report we demonstrate that the cytokine combination of human recombinant interleukin 1 beta (IL-1 beta), tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma) induces the formation of nitric oxide by human islets. This combination of cytokines stimulates both the formation of the nitric oxide derivative, nitrite, and the accumulation of cGMP by human islets. The nitric oxide synthase inhibitor NG-monomethyl-L-arginine prevents formation of both cGMP and nitrite. IL-1 beta and IFN-gamma are sufficient to induce nitric oxide formation by human islets, whereas TNF-alpha potentiates nitrite production. This combination of cytokines (IL-1 beta, TNF-alpha, and IFN-gamma) also influences insulin secretion by human islets. Pretreatment of human islets with low concentrations of this cytokine combination (IL-1 beta at 15 units/ml, 0.7 nM TNF-alpha, and IFN-gamma at 150 units/ml) appears to slightly stimulate insulin secretion. Higher concentrations (IL-1 beta at 75 units/ml, 3.5 nM TNF-alpha, and IFN-gamma at 750 units/ml) inhibit insulin secretion from human islets, and the inhibitory effect is prevented by NG-monomethyl-L-arginine. This higher concentration of cytokines also induces the formation of an electron paramagnetic resonance-detectable g = 2.04 axial feature by human islets that is characteristic of the formation of an iron-dithio-dinitrosyl complex. The formation of this complex is prevented by NG-monomethyl-L-arginine, thus confirming that this cytokine combination induces the formation of nitric oxide by human islets. These results indicate that nitric oxide mediates the inhibitory effects of cytokines on glucose-stimulated insulin secretion by human islets and suggest that nitric oxide may participate in beta-cell dysfunction associated with insulin-dependent diabetes mellitus.
Author List
Corbett JA, Sweetland MA, Wang JL, Lancaster JR Jr, McDaniel MLAuthor
John A. Corbett PhD Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ArginineCyclic GMP
Diabetes Mellitus, Type 1
Electron Spin Resonance Spectroscopy
Humans
In Vitro Techniques
Insulin
Interferon-gamma
Interleukin-1
Islets of Langerhans
Nitric Oxide
Nitrites
Recombinant Proteins
Secretory Rate
Tumor Necrosis Factor-alpha
omega-N-Methylarginine
