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Pentoxifylline promotes replication of human cytomegalovirus in vivo and in
vitro
K Staak, S Prosch, J Stein, C Priemer, R Ewert, WD Docke, DH Kruger, HD Volk and P Reinke
Institute of Medical Virology, Medical Clinic V-Nephrology, Medical Faculty
(Charite), Humboldt Universitat zu Berlin, Germany.
OKT3 monoclonal antibody (MoAb) therapy is well established in the
prevention and therapy of acute rejection in transplant patients.
Unfortunately, this therapy is associated with several short-term (cytokine
release syndrome) and long-term (infections, EBV-related lymphoma) side
effects. Recently, we were able to demonstrate an association between the
TNF alpha release following the first OKT3 MoAb infusions and the
appearance of human cytomegalovirus (HCMV) reactivation several days later.
In order to prevent this TNF alpha associated HCMV reactivation patients
were additionally treated with pentoxifylline (PTX), a methylxanthine
derivative that has been shown to suppress TNF alpha induction. Although
the TNF alpha peak plasma level following OKT3 MoAb treatment was markedly
reduced, the incidence of HCMV reactivation and HCMV disease was not
influenced. In transient transfection experiments using HCMV immediate
early enhancer/promoter CAT reporter gene constructs PTX enhanced the
promoter activity independently from TNF alpha in premonocytic cells.
Furthermore, PTX acted synergistically with TNF alpha. In virus-infected
human embryonal lung fibroblasts HCMV replication was triggered in the
presence of both PTX and TNF alpha, while either substance alone had only
marginal effects. The stimulatory effect of PTX on the immediate early (IE)
enhancer/promoter was mediated via CREB/ ATF, a eukaryotic transcription
factor that binds to the 19 bp sequence motif in the enhancer region, while
TNF alpha stimulation was mediated by activation of the transcription
factor NF-kappaB and its binding to the 18 bp sequence motif in the
enhancer. These data suggest a potential side effect of cAMP-elevating
drugs such as PTX.
Volume 89,
Issue 10,
pp. 3682-3690,
05/15/1997
Copyright © 1997 by The American Society of Hematology
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