Pentoxifylline differentially regulates migration and respiratory burst activity of the neutrophil.

Abstract

TNF is produced by monocytes/macrophages in response to endotoxin, which may lead to septic shock. TNF stimulates neutrophil adherence, degranulation, and superoxide production, but inhibits neutrophil migration. A mitigating anti-inflammatory effect can be experimentally induced in septic shock by TNF blockers, such as pentoxifylline, and is also suggested for treatment with hrG-CSF. With regard to the combination of pentoxifylline and hrG-CSF, the purpose of this investigation was to explore whether and in what way the effects of hrG-CSF and pentoxifylline interact with each other in neutrophils. To this end, we studied the effects of pentoxifylline on TNF- and G-CSF-induced modulation of neutrophil chemotaxis and O2 release. TNF and G-CSF decreased directed migration of neutrophils to FMLP or IL-8. High-dose pentoxifylline (1 mM) was able to counteract the effect of TNF but not that of G-CSF on neutrophil migration. In the presence of pentoxifylline, TNF and G-CSF were unable to stimulate respiratory burst. In contrast, pre-exposure of cells to pentoxifylline followed by washing increased the priming effect of TNF or hrG-CSF on neutrophil respiratory burst activity. The methylxanthine derivative by itself showed no effect on spontaneous and fMLP-stimulated O2 release by neutrophils. Stimulation of neutrophil respiratory burst by pentoxifylline may not be detectable in the presence of pentoxifylline due to its known oxygen-radical scavenging function. Results suggest that by blocking the inflammatory action of TNF on neutrophils, pentoxifylline may diminish endothelial cell damage caused by inhibited neutrophil chemotaxis. On the other hand, since transiently present pentoxifylline may enhance the respiratory burst activity of TNF- or hrG-CSF-primed neutrophils, concomitant administration of pentoxifylline and hrG-CSF to patients with SIRS/sepsis might diminish beneficial effects of the latter and additional deleterious effects might occur.