A Protective Role for Heme Oxygenase Expression in Pancreatic Islets Exposed to Interleukin-1β**This work was supported by NIH Grant DK-25705 (to S.G.L.).

Abstract Heme oxygenase (HO)-1 expression was investigated in rat isolated pancreatic islets. Freshly isolated islets showed no evidence of HO-1 expression. After a 20-h culture, there was a small increase in HO-1 in control islets, and interleukin-1β (IL-1β) induced HO-1 expression above control levels. NG-monomethyl-l-arginine inhibited the IL-1β-induced increase in HO-1. Sodium nitroprusside-generated nitric oxide also increased HO-1 expression. CoCl2 induced a concentration- and time-dependent increase in HO-1, but not heat shock protein 70, expression. Cobalt chloride (CoCl2) protected islets from the inhibitory effects of IL-1β on glucose-stimulated insulin release and glucose oxidation. Nickel chloride did not mimic the effects of CoCl2. An inhibitor of HO-1 activity, zinc-protoporphyrin IX (ZnPP), prevented the protective effect of CoCl2 on insulin release with IL-1β but did not affect HO-1 expression or the inhibitory response to IL-1β alone. ZnPP also inhibited the protective effect of hemin in IL-1β-treated islets. CoCl2 inhibited the marked increase in islet nitrite production in response to IL-1β. Cobalt-protoporphyrin IX (CoPP), which increased HO expression and activity, also protected islets from the inhibitory effects of IL-1β, even though IL-1β largely blocked the CoPP-induced increase in HO-1 expression. In βHC9 cells, CoCl2 increased HO-1 expression and HO activity, whereas CoPP directly activated HO. ZnPP inhibited basal and CoCl2-stimulated HO activity. Thus, increased HO-1 expression and/or HO activity in response to CoCl2, CoPP, and hemin, seems to mediate protective responses of pancreatic islets against IL-1β. HO-1 may be protective of β-cells because of the scavenging of free heme, the antioxidant effects of the end-product bilirubin, or the generation of carbon monoxide, which might have insulin secretion-promoting effects and inhibitory effects on nitric oxide synthase.

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Reciprocal regulation of airway rejection by the inducible gas-forming enzymes heme oxygenase and nitric oxide synthase

Journal of Experimental Medicine ◽

10.1084/jem.20050377 ◽

2005 ◽

Vol 202 (2) ◽

pp. 283-294 ◽

Cited By ~ 33

Author(s):

Kanji Minamoto ◽

Hiroaki Harada ◽

Vibha N. Lama ◽

Maksim A. Fedarau ◽

David J. Pinsky

Keyword(s):

Nitric Oxide ◽

Heme Oxygenase ◽

Soluble Guanylate Cyclase ◽

Protoporphyrin Ix ◽

Competitive Inhibitor ◽

Binding Activity ◽

Zinc Protoporphyrin ◽

Reciprocal Regulation ◽

Enhanced Expression ◽

Lung Transplant Recipients

Obliterative bronchiolitis (OB) develops insidiously in nearly half of all lung transplant recipients. Although typically preceded by a CD8+ T cell–rich lymphocytic bronchitis, it remains unresponsive to conventional immunosuppression. Using an airflow permissive model to study the role of gases flowing over the transplanted airway, it is shown that prolonged inhalation of sublethal doses of carbon monoxide (CO), but not nitric oxide (NO), obliterate the appearance of the obstructive airway lesion. Induction of the enzyme responsible for the synthesis of CO, heme oxygenase (Hmox) 1, increased carboxyhemoglobin levels and suppressed lymphocytic bronchitis and airway luminal occlusion after transplantation. In contrast, zinc protoporphyrin IX, a competitive inhibitor of Hmox, increased airway luminal occlusion. Compared with wild-type allografts, expression of inducible NO synthase (iNOS), which promotes the influx of cytoeffector leukocytes and airway graft rejection, was strikingly reduced by either enhanced expression of Hmox-1 or exogenous CO. Hmox-1/CO decreased nuclear factor (NF)-κB binding activity to the iNOS promoter region and iNOS expression. Inhibition of soluble guanylate cyclase did not interfere with the ability of CO to suppress OB, implicating a cyclic guanosine 3′,5′-monophosphate–independent mechanism through which CO suppresses NF-κB, iNOS transcription, and OB. Prolonged CO inhalation represents a new immunosuppresive strategy to prevent OB.

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Interleukin 10 inhibits insulin release from and nitric oxide production in rat pancreatic islets

Acta Endocrinologica ◽

10.1530/eje.0.1350374 ◽

1996 ◽

Vol 135 (3) ◽

pp. 374-378 ◽

Cited By ~ 6

Author(s):

Renato Laffranchi ◽

Giatgen A Spinas

Keyword(s):

Nitric Oxide ◽

Pancreatic Islets ◽

Insulin Release ◽

Interleukin 10 ◽

Interleukin 1Β ◽

Nitric Oxide Production ◽

Β Cell ◽

Cell Dysfunction ◽

Rat Pancreatic Islets ◽

Oxide Production

Laffranchi R, Spinas GA. Interleukin 10 inhibits insulin release from and nitric oxide production in rat pancreatic islets. Eur J Endocrinol 1996;135:374–8. ISSN 0804–4643 Interleukin 10 was found to prevent cytokine-induced nitric oxide production in murine macrophages. Because, in rat islets, interleukin 1β induces β-cell dysfunction, mainly due to overproduction of nitric oxide, we studied if this effect could be counteracted by interleukin 10. Rat pancreatic islets were cultured for 24 h in the presence or absence of 0.02–20 ng/ml recombinant human interleukin 10. Interleukin 10 dose-dependently inhibited insulin secretion with maximal inhibition (27 ±4%, p < 0.05) at 2 ng/ml without impairment of islet cell viability. However, incubation of pancreatic islets with interleukin 10 resulted in a 61.5% decrease of nitric oxide production. Co-incubation of islets with interleukin 10 (2 ng/ml) and recombinant human interleukin 1β (0.15 ng/ml) resulted in a more pronounced suppression of basal insulin release than with interleukin 1β alone (55 ± 3.6% vs 44 ± 3.6% with interleukin 1β alone, p < 0.05) but did not reduce interleukin 1β-stimulated NO production or reverse the effect of interleukin 1β on cell viability. Thus, in pancreatic islets interleukin 10 is not capable of counteracting the interleukin 1β-induced β-cell dysfunction, but rather enhances the inhibitory effect of interleukin 1β by a different mechanism. Renato Laffranchi, Division of Endocrinology and Metabolism, Department of Internal Medicine, University Hospital, Rämistrasse 100, CH-8091 Zürich, Switzerland

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Inhibitory effects of epicatechin on interleukin-1β-induced inducible nitric oxide synthase expression in RINm5F cells and rat pancreatic islets by down-regulation of NF-κB activation

Biochemical Pharmacology ◽

10.1016/j.bcp.2004.06.031 ◽

2004 ◽

Vol 68 (9) ◽

pp. 1775-1785 ◽

Cited By ~ 41

Author(s):

Myung-Jun Kim ◽

Gyeong Ryul Ryu ◽

Jung-Hoon Kang ◽

Sang Soo Sim ◽

Do Sik Min ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Pancreatic Islets ◽

Inducible Nitric Oxide Synthase ◽

Interleukin 1Β ◽

Inhibitory Effects ◽

Rinm5f Cells ◽

Rat Pancreatic Islets ◽

Oxide Synthase ◽

Inducible Nitric Oxide

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Testosterone Rapidly Stimulates Insulin Release from Isolated Pancreatic Islets through a Non-genomic Dependent Mechanism

Hormone and Metabolic Research ◽

10.1055/s-2005-870575 ◽

2005 ◽

Vol 37 (11) ◽

pp. 662-665 ◽

Cited By ~ 25

Author(s):

M. L. Grillo ◽

A. P. Jacobus ◽

R. Scalco ◽

F. Amaral ◽

D. O. Rodrigues ◽

...

Keyword(s):

Pancreatic Islets ◽

Insulin Release ◽

Isolated Pancreatic Islets ◽

Dependent Mechanism

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The possible mechanisms by which phanoside stimulates insulin secretion from rat islets

Journal of Endocrinology ◽

10.1677/joe.1.06948 ◽

2007 ◽

Vol 192 (2) ◽

pp. 389-394 ◽

Cited By ~ 26

Author(s):

Nguyen Khanh Hoa ◽

Åke Norberg ◽

Rannar Sillard ◽

Dao Van Phan ◽

Nguyen Duy Thuan ◽

...

Keyword(s):

Insulin Secretion ◽

B Cells ◽

Pancreatic Islets ◽

Insulin Release ◽

Pertussis Toxin ◽

Insulin Response ◽

Gk Rat ◽

Isolated Pancreatic Islets ◽

Gk Rats ◽

Rat Islets

We recently showed that phanoside, a gypenoside isolated from the plant Gynostemma pentaphyllum, stimulates insulin secretion from rat pancreatic islets. To study the mechanisms by which phanoside stimulates insulin secretion. Isolated pancreatic islets of normal Wistar (W) rats and spontaneously diabetic Goto-Kakizaki (GK) rats were batch incubated or perifused. At both 3.3 and 16.7 mM glucose, phanoside stimulated insulin secretion several fold in both W and diabetic GK rat islets. In perifusion of W islets, phanoside (75 and 150 μM) dose dependently increased insulin secretion that returned to basal levels when phanoside was omitted. When W rat islets were incubated at 3.3 mM glucose with 150 μM phanoside and 0.25 mM diazoxide to keep K-ATP channels open, insulin secretion was similar to that in islets incubated in 150 μM phanoside alone. At 16.7 mM glucose, phanoside-stimulated insulin secretion was reduced in the presence of 0.25 mM diazoxide (P<0.01). In W islets depolarized by 50 mM KCl and with diazoxide, phanoside stimulated insulin release twofold at 3.3 mM glucose but did not further increase the release at 16.7 mM glucose. When using nimodipine to block L-type Ca2+ channels in B-cells, phanoside-induced insulin secretion was unaffected at 3.3 mM glucose but decreased at 16.7 mM glucose (P<0.01). Pretreatment of islets with pertussis toxin to inhibit exocytotic Ge-protein did not affect insulin response to 150 μM phanoside. Phanoside stimulated insulin secretion from Wand GK rat islets. This effect seems to be exerted distal to K-ATP channels and L-type Ca2+ channels, which is on the exocytotic machinery of the B-cells.

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Nitric oxide donor SIN-1 inhibits insulin release

AJP Cell Physiology ◽

10.1152/ajpcell.1996.271.4.c1098 ◽

1996 ◽

Vol 271 (4) ◽

pp. C1098-C1102 ◽

Cited By ~ 29

Author(s):

A. Sjoholm

Keyword(s):

Nitric Oxide ◽

Diabetes Mellitus ◽

Protein Kinase C ◽

Insulin Secretion ◽

Protein Kinase ◽

Beta Cell ◽

Pancreatic Islets ◽

Insulin Release ◽

Kinase C ◽

Stimulus Secretion Coupling

Preceding the onset of insulin-dependent diabetes mellitus, pancreatic islets are infiltrated by macrophages secreting interleukin-1 beta, which exerts cytotoxic and inhibitory actions on islet beta-cell insulin secretion through induction of nitric oxide (NO) synthesis. The influence of the NO donor 3-morpholinosydnonimine (SIN-1) on insulin secretion from isolated pancreatic islets in response to various secretagogues was investigated. Stimulation of insulin release evoked by glucose, phospholipase C activation with carbachol, and protein kinase C activation with phorbol ester were obtained by SIN-1, whereas the response to adenylyl cyclase activation or K(+)-induced depolarization was not affected. It is concluded that enzymes involved in glucose catabolism, phospholipase C or protein kinase C, may be targeted by NO. Reversal of SIN-1 inhibition of glucose-stimulated insulin release by dithiothreitol suggests that NO may inhibit insulin secretion partly by S-nitrosylation of thiol residues in key proteins in the stimulus-secretion coupling. These adverse effects of NO on the beta-cell stimulus-secretion coupling may be of importance for the development of the impaired insulin secretion characterizing diabetes mellitus.

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