Inhibitors of Phosphodiesterase Isoforms III or IV Suppress Islet-Cell Nitric Oxide Production

Abstract

SUMMARY: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. (Lab Invest 2001, 81:1109 -1117.

The inhibitory effects of roflumilast on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells are mediated by heme oxygenase-1 and its product carbon monoxide

“…Although rofl umilast has benefi cial biological effects, its mechanism in infl ammatory cells has not yet been clearly demonstrated. It was recently reported that rolipram, a PDE4 specifi c inhibitor, and pentoxifylline, a general PDE inhibitor, suppressed NO production in islet cells [27] and macrophages [28].…”

Cyclic nucleotide phosphodiesterases in pancreatic islets

“…While this effect can be explained by inhibition of cytokine production by pro-inflammatory cells such as macrophages there could also be a contribution from an inhibition of nitric oxide production by islet cells in response to cytokines. Thus pentoxifylline and the selective PDE3 inhibitor cilostamide blocked nitric oxide production by mouse islet cells and a beta-cell line (NIT-1) in response to stimulation by lipopolysaccharide and inflammatory cytokines [96] and prevented the expression of inducible nitric oxide synthase both in vitro and in vivo in the NOD mouse. This supports earlier findings that IBMX reduced IL-1β induced nitric oxide synthase expression and nitric oxide production in rat islets, an effect mimicked by dibutyryl cyclic AMP [41].…”

Targeting β-cell cyclic 3′5′adenosine monophosphate for the development of novel drugs for treating type 2 diabetes mellitus. A review

“…While this effect may be explained by inhibition of cytokine production by pro-inflammatory cells such as macrophages, there may also be a contribution from an inhibition of nitric oxide production by islet cells in response to cytokines. Thus pentoxifylline and the selective PDE3 inhibitor cilostamide blocked nitric oxide production by mouse islet cells and a -cell line (NIT-1) in response to stimulation by lipopolysaccharide and inflammatory cytokines (Besay & Prud'homme 2001) and prevented the expression of inducible nitric oxide synthase both in-vitro and invivo in the NOD mouse. This supports earlier findings that IBMX reduced interleukin-1-induced nitric oxide synthase expression and nitric oxide production in rat islets, an effect mimicked by dibutyryl cAMP (Andersen et al 1996).…”