Pentoxifylline in vivo down-regulates the release of IL-1 beta, IL-6, IL-8 and tumour necrosis factor-alpha by human peripheral blood mononuclear cells

Abstract

Pentoxifylline (PTX) is a methylxanthine compound known to inhibit the production of tumour necrosis factor-alpha (TNF-alpha), which is an important inflammatory mediator. There is also recent evidence that PTX may influence other inflammatory cytokines, such as interleukin-1 (IL-1) and IL-6. Due to the therapeutic implications, the present study addressed the in vivo effects of PTX on the release of TNF-alpha, IL-1 beta, IL-6 and IL-8 by human peripheral blood mononuclear cells (PBMC). When PBMC were obtained from healthy volunteers ingesting 5 x 400 mg PTX orally for 2 days, the ability of PBMC cultured for 24 hr to release TNF-alpha was significantly reduced, while secretion of IL-1 beta, IL-6 and IL-8 was not affected. However, when PBMC were obtained from the same individuals 5 days after PTX had been stopped, the release of all four cytokines was significantly suppressed. This effect appeared to be exerted at the transcriptional level, since Northern blot analysis revealed reduced cytokine transcripts. In order to gain more insight into the effect of PTX on cytokine release, PBMC were obtained from normal volunteers, either stimulated with lipopolysaccharide (LPS) or left unstimulated, and subsequently incubated in vitro with PTX for 48 hr. Under these conditions, only TNF-alpha was found to be reduced by PTX, while IL-1 beta and IL-8 were not affected, IL-6 was even enhanced. However, when PBMC were incubated with PTX for 24 hr, PTX removed thereafter by medium change and cells further cultured, the production not only of TNF-alpha but also of IL-1 beta, IL-6 and IL-8 was reduced, demonstrating that PTX exerts diverse (inhibitory) effects on cytokine release by PBMC.