title: Influence of pentoxifylline on natural cytotoxicity and expression of granzymes and PI-9, a specific granzyme B inhibitor.
abstract: Pentoxifylline (PTX) is an unspecific inhibitor of phosphodiesterase activity that increases intracellular concentration of cyclic nucleotides, mainly cAMP. Since PTX improves microcirculatory blood flow, it is commonly and often chronically used in peripheral vascular diseases. On the other hand PTX also displays a variety of immunomodulatory activities. PTX inhibits natural cytotoxicity and it has previously been suggested that it could partially act also through its influence on perforin/granzyme-dependent pathways. However, the underlying mechanisms are obscure and it remains unknown whether PTX inhibits natural cytotoxicity influencing only leukocytes or also acting on target cells. In this study, we show that PTX inhibits expression of granzyme A in human leukocytes probably due to suppression of phosphodiesterase activity. Contrary, PTX does not affect expression of granzyme B and H. On the other hand we hypothesized that PTX could inhibit natural cytotoxicity not only affecting leukocytes but also due to generation of resistance to leukocyte-mediated cytotoxicity in target cells e.g. through overexpression of PI-9, a specific granzyme B inhibitor. We found that at the mRNA level, PTX stimulates expression of PI-9 in K562 cells. However, we did not observe such an influence at the protein level, in either K562 cells or in human leukocytes. It may suggest that other PTX-triggered molecular events may interfere with PI-9 overexpression in these cells at the further, post-transcriptional levels. According to these results, PTX did not affect resistance of target cells to natural cytotoxicity. Altogether, PTX inhibits natural cytotoxicity affecting mainly effector but not target cells and in case of the effector cells, besides previously reported mechanisms, it can also inhibit granzyme A expression.
authors.affiliation: Department of Histology and Embryology, Center of Biostructure Research, The Medical University of Warsaw, PL 02004 Warsaw, Poland. ml@plusnet.pl
authors.forename: Maciej
authors.initials: M
authors.lastname: Lazarczyk
authors.forename: Piotr
authors.initials: P
authors.lastname: Dziunycz
authors.forename: Justyna
authors.initials: J
authors.lastname: Niderla
authors.forename: Lukasz
authors.initials: L
authors.lastname: Milewski
authors.forename: Marta Alicja
authors.initials: MA
authors.lastname: Lazarczyk
authors.forename: Anna
authors.initials: A
authors.lastname: Boszczyk
authors.forename: Robert
authors.initials: R
authors.lastname: Samaha
authors.forename: Tomasz
authors.initials: T
authors.lastname: Grzela
mesh_terms: D003994:Bucladesine / Q000378:metabolism; D053804:Granzymes; D006801:Humans; D020014:K562 Cells; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D010431:Pentoxifylline / Q000378:metabolism*; D037342:Pertussis Toxin / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000378:metabolism*; D015843:Serpins / Q000378:metabolism*
chemical_list: D010726:Phosphodiesterase Inhibitors; C102316:SERPINB9 protein, human; D015842:Serine Proteinase Inhibitors; D015843:Serpins; D003994:Bucladesine; D037342:Pertussis Toxin; C509213:GZMB protein, human; C069434:GZMH protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; C509212:GZMA protein, human; D010431:Pentoxifylline