Inhibition of insulin secretion by interleukin‐1β and tumour necrosis factor‐α via an L‐arginine‐dependent nitric oxide generating mechanism

Abstract

Inhibition of glucose‐induced insulin secretion by interleukin‐1β (IL‐1β), or IL‐1β plus tumour necrosis factor‐α (TNF‐α), was less marked when rat islets of Langerhans were cultured for 12 h with these cytokines in L‐arginine‐free medium as opposed to medium containing L‐arginine (1 mM). Inhibition of secretion by IL‐1β was further alleviated when islets were maintained in L‐arginine‐free medium supplemented with N‐ω‐nitro‐L‐arginine methyl ester (NAME), while synergism between IL‐1β plus TNF‐α was completely abolished. Tissue culture medium nitrite levels were raised in islets treated with IL‐1β or TNF‐α (48 h). Cytokine‐stimulated nitrite production was not observed in islets cultured with NAME (1 mM). In conclusion, an L‐arginine‐dependent nitric oxide generating mechanism is involved in the inhibition of insulin secretion by IL‐1β, and accounts for the phenomenon of synergism between IL‐1β and TNF‐α.

Cytotoxic action of IL‐1β against pancreatic islets is mediated via nitric oxide formation and is inhibited by NG‐monomethyl‐l‐arginine

“…the modulation of insulin secretion after glucose challenge, also have been reported [7,10]. And it was shown very recently that the 1L-1/~-induced inhibition of insulin secretion is also reversible by adding NMA [14,15]. Islets contain a dense capillary network [I 6] and endothelial cells have been shown to be inducible for generating large amounts of nitric oxide by cytokines, eSl~-cially IL-1]~ in synergny with TNF~ and/or IFN-7 [17][18][19][20].…”

Inhibition of IFN-γ-induced STAT1 activation by 15- deoxy-Δ12,14-prostaglandin J2

“…Evidence to support a role for iNOS and nitric oxide in cytokine-mediated ␤-cell damage includes the following: 1) the ability of iNOS inhibitors to prevent the inhibitory actions of these cytokines on insulin secretion, islet oxidative metabolism, and islet degeneration (7,9,36); 2) the inability of cytokines to impair glucose-induced insulin secretion by islets isolated from iNOS-deficient mice (13); and 3) the induction of diabetes in transgenic mice expressing iNOS under control of the rat insulin promoter (40). In the current study, we show that PGJ 2 is a potent inhibitor of IL-1-and IFN-␥-stimulated signaling pathways as well as the downstream activation of iNOS expression in islets and RINm5F cells.…”

“…Treatment of rat islets with IL-1 results in a timeand concentration-dependent inhibition of glucosestimulated insulin secretion that is followed by islet degeneration (8,22,29). The inhibitory and destructive actions of IL-1 on ␤-cell function correlate with the time-dependent expression of inducible nitric oxide synthase (iNOS) and production of nitric oxide and can be prevented by inhibitors of iNOS (10,12,36). Alone, interferon (IFN)-␥ does not appear to modulate ␤-cell function; however, IFN-␥ has been shown to both prime and potentiate the stimulatory actions of IL-1 on iNOS expression by rat islets (19,21).…”

Coptidis rhizoma extract protects against cytokine-induced death of pancreatic β-cells through suppression of NF-κ B activation

“…Nitric oxide is a short-lived and highly reactive radical, which inhibits the Krebs-cycle enzyme aconitase and electron transport chain complexes I and II, resulting in reduced glucose oxidation rates, ATP generation, and insulin production (Welsh et al, 1991;Corbett et al, 1992;Cunningham and Green, 1994). In fact, iNOS inhibitors, such as N w -nitro-Larginine methylester (L-NAME) and aminoguanidine, attenuate cytokine-induced -cell dysfunction and islet degeneration (Southern et al, 1990;Welsh et al, 1991;Eizirik et al, 1996).…”