Inhibitors of phosphodiesterase isoforms III or IV suppress islet-cell nitric oxide production.
The general phosphodiesterase (PDE) inhibitor pentoxifylline (PTX), and the PDE type IV inhibitor rolipram (ROL), both increase intracellular cAMP levels and suppress inflammatory cytokine production by T cells and macrophages. We have previously shown that PTX and ROL protect from autoimmune diabetes in nonobese diabetic (NOD) mice. These drugs may mediate some of their anti-inflammatory effects by blocking nitric oxide (NO) production by macrophages. In this study, we investigated the effect of PDE inhibitors in blocking NO production by insulin-secreting NIT-1 insulinoma cells and mouse islet cells in vitro and in vivo. Insulinoma cells and islet cells produced NO when stimulated with a combination of inflammatory cytokines and lipopolysaccharide (LPS). We found that both PTX and ROL markedly suppressed this induced NO production. Islet cells express PDEs III and IV and, accordingly, the PDE III inhibitor cilostamide (CIL) also suppressed NO production, and a combination of ROL and CIL had a synergistic effect. This suppression appeared to be mediated, at least in part, by elevating cAMP level and was mimicked by other cAMP-elevating agents, ie, membrane-permeable cAMP analogs (dibutyryl cAMP and 8-bromo cAMP) and an adenylate cyclase stimulator (forskolin). PDE inhibitors suppressed the expression of inducible nitric oxide synthase (iNOS) mRNA. In vivo treatment with PTX or ROL prevented iNOS protein expression in the islets of NOD mice with cyclophosphamide-accelerated disease. Our findings suggest that PDE inhibitors can protect islets against autoimmunity.
Beshay
E
E
Department of Pathology, McGill University, Montreal, Quebec, Canada.
Prud'homme
G J
GJ
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D002478:Cells, Cultured; D046508:Culture Techniques; D000242:Cyclic AMP / Q000096:biosynthesis; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D005260:Female; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D010431:Pentoxifylline / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D020889:Rolipram / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D010726:Phosphodiesterase Inhibitors; D015363:Quinolones; D012333:RNA, Messenger; D009569:Nitric Oxide; C021294:cilostamide; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; D010431:Pentoxifylline