Pentoxifylline potentiates nitric oxide production and growth suppression in interferon-gamma-treated L929...

In this study the effects of the phosphodiesterase inhibitor pentoxifylline (PTX) on nitric oxide (NO) production and proliferation of murine fibrosarcoma cell line L929 were investigated. We showed that both IFN-gamma (200 U/ml)-induced NO production and inhibition of [3H]thymidine uptake by L929 cells were potentiated in a synergistic fashion in the presence of PTX (200 micrograms/ml). These effects of PTX could be a consequence of phosphodiesterase inhibition, since they were mimicked by cAMP analogue dibutyryl cAMP. PTX failed to affect NO production when added to cells in which inducible NO synthase (iNOS) had already been induced with IFN-gamma and any further induction was blocked by cycloheximide (1 ug/ml), indicating that PTX modulates NO synthesis in L929 cells probably on a pretranslational level. Inhibition of iNOS with L-NAME (3 mM), although completely abolishing NO production, did not have any effect on proliferation of IFN-gamma or IFN-gamma + PTX-treated L929 cells, arguing against the possibility that growth suppression of these cells was due to the enhanced NO production. Moreover, the observation that the NO donor sodium nitroprusside (10-250 microM) significantly increased incorporation of [3H]thymidine in L929 fibroblasts suggests a role for NO in the positive regulation of their growth.