Interleukin-1β-induced nitric oxide production from isolated rat islets is modulated by D-glucose and 3-isobutyl-1-methyl xanthine

Abstract

Interleukin-1 beta has been proposed to cause selective beta-cell destruction via the induction of nitric oxide synthesis. The cytotoxic effect of interleukin-1 beta is modulated by the concentration of D-glucose in the medium. The aim of this study was to investigate if D-glucose-mediated modulation of interleukin-1 beta effects on insulin release from isolated rat islets was related to modulation of nitric oxide production. Further, we wished to investigate the effects of agents increasing the intracellular concentration of cAMP on interleukin-1 beta-induced nitrite production. We demonstrated that D-glucose potentiated interleukin-1 beta-induced nitrite production in rat islets without affecting the mRNA level of the inducible nitric oxide synthase. This effect was dissociated from interleukin-1 beta action on insulin release, since a relative protection against interleukin-1 beta effects on acute insulin release was found at high (28 mmol/l) concentrations of D-glucose, and blocking nitrite production by the L-arginine analog aminoguanidine, which selectively inhibits the cytokine-inducible nitric oxide synthase, did not result in protection against the inhibitory action of interleukin-1 beta. Neither L-glucose nor the secretagogues L-leucine, tolbutamide and 3-isobutyl-1-methyl xanthine shared the potentiating effect of D-glucose. The phosphodiesterase inhibitor 3-isobutyl-1-methyl xanthine reduced interleukin-1 beta-induced nitrite production at 3.3 mmol/l D-glucose, an effect that could be reproduced by the cAMP analog dibutyryl cAMP. Addition of 3-isobutyl-1-methyl xanthine resulted in a threefold reduction in the mRNA level of interleukin-1 beta-induced inducible nitric oxide synthase. We conclude that interleukin-1 beta-induced islet nitric oxide synthesis is augmented by D-glucose, but not by non-substrate secretagogues, and that secretagogues that elevate cAMP inhibit islet nitric oxide production.

Suppression of Astroglial Nitric Oxide Synthase Expression by Norepinephrine Results from Decreased NOS‐2 Promoter Activity

“…The effect was dose dependent, with an IC 50 value of 100 nM, mediated via /3-adrenergic receptor stimulation and replicated by the cyclic AMP (cAMP) analogue dbcAMP. Our initial observations in astrocytes, one of the first to demonstrate that cAMP could be a suppressive modulator of NOS-2 expression, have recently been confirmed by a second group (Pahan et al, 1997), and suppressive effects of cAMP on NOS-2 expression have been described for several other cell types (Bulut et al, 1993;Raddassi et al, 1993;Messmer and Brune, 1994;Harbrecht et al, 1995;Andersen et al, 1996;Minghetti et al, 1997). In astrocytes, other neurotransmitters, including glutamate and ATP (Park et al, 1994;Murphy et al, 1995) and angiotensin II (Chandler et al, 1995), also decrease astroglial NOS-2 expression.…”

“…Initial reports showed that prostaglandins, which can elevate intracellular cAMP levels, reduced NOS-2 induction and that inhibitors of adenylate cyclase prevented prostaglandin effects (Marotta et al, 1992;Bulut et al, 1993;Raddassi et al, 1993;Harbrecht et al, 1996;Minghetti et al, 1997). More direct evidence that elevated cAMP levels can block NOS-2 induction comes from studies using lipophilic cAMP analogues (forskolin, dbcAMP) and /3-adrenergic agofists (isoproterenol) both in vitro (Raddassi et al, 1993;Messmer and Brune, 1994;Andersen et al, 1996;Minghetti et al, 1997) as well as in vivo (Szabo et al, 1997). There is hence compelling evidence that cAMP can act as a suppressor of cytokine-dependent NOS-2 induction.…”

Cyclic nucleotide phosphodiesterases in pancreatic islets

“…Regulation of gene expression by cyclic AMP could have relevance to effects on beta-cell growth, differentiation and apoptosis. For example, increased cyclic AMP concentrations protected rat islets against interleukin-1 beta mediated induction of nitric oxide synthase and nitric oxide production [41]. Excessive nitric oxide production seems to mediate subsequent apoptosis of beta cells.…”

Suppressor of cytokine signaling 3 (SOCS-3) protects β-cells against interleukin-1β- and interferon-γ-mediated toxicity

“…Islets from 3-6-day-old Wistar Furth rats (Charles River Germany, Sulzfeldt) were isolated and cultured as described (13,14). INS-1 and INS-r3#2 cells were cultured in RPMI 1640 medium with Glutamax-I (GIBCO͞BRL Life Technologies), supplemented with 10% TeT System Approved FBS (CLONTECH), selected for low tetracycline content, and supplemented with penicillin, streptomycin (GIBCO͞BRL), and 50 M ␤-mercaptoethanol (Sigma) under standard cell culture conditions (15,16).…”