Mediator-dependent effects of pentoxifylline on endothelium for transmigration of neutrophils

In the present study, we investigated the effects of the anti-inflammatory drug pentoxifylline (PTX) on activation of endothelial cells for enhanced a dhesion and transmigration of neutrophils by lipopolysaccharide (LPS), tumo r necrosis factor-alpha (TNF), interleukin-1 (IL-1) and granulocyte colony- stimulating factor (G-CSF). To evaluate the mechanism by which PTX exerts i ts effect, human umbilical vein endothelial cells (HUVEC) were pretreated w ith theophylline, 2'-O-dibutyryl-3', T-cyclic adenosine monophosphate (db c AMP), and 3-isobutyl-1-methylxanthine, respectively, prior to stimulation. Pretreatment of HUVEC with PTX significantly antagonized TNF-, IL-1-, and G -CSF-activated transmigration of neutrophils. Additive stimulatory effects of PTX were seen with LPS. With the exception of theophylline, all other te st cAMP-raising agents stimulated transmigration in similar fashion to PTX. Upon stimulation with TNF or LPS, HUVEC produced IL-8 and PTX affected thi s process in opposing fashions, with inhibition of the effects of TNF and a ugmentation of those of LPS. These results demonstrate that PTX differentia lly affects mediator-induced activation of HUVEC. The present IL-8 dependen t and cAMP-regulated augmentation of LPS-induced stimulation of transmigrat ion is the first description of an additive effect of PTX with a pro-inflam matory agent. (C) 1999 Elsevier Science B.V. All rights reserved.