Influence of pentoxifylline on perforin expression in human PBMC

Pentoxifylline (PTX) is a methylxanthine derivative that unspecifically inhibits phosphodiesterase activity and thus, it increases intracellular concentration of cyclic nucleotides. Currently, PTX is commonly and chronically used in peripheral blood vessel diseases. Besides its well-known influence on rheologic properties of blood, PTX has also been found to decrease secretion of some cytokines such as IL-12, TNF and IFN-gamma and thus it could exert immunomodulatory activity. Furthermore, PTX inhibits lymphocyte cytotoxicity affecting the perforin-dependent pathway, both in humans and animals. It has also been shown recently that in some murine models, PTX promotes tumor growth. Such a phenomenon, at least partially, could result from PTX-dependent inhibition of natural cytotoxicity. However, the detailed mechanism of PTX influence on cytotoxic activity in humans has not been established. We hypothesized that PTX-dependent inhibition of natural cytotoxicity could result from decrease in perforin expression. In this study, it was shown that pentoxifylline only moderately inhibits perforin expression at the mRNA level in human peripheral blood mononuclear cells (PBMC), and this effect seems to be independent of intracellular cAMP concentration. On the other hand, PTX did not significantly influence perforin expression at the protein level. These results suggest that in humans, contrary to murine models, inhibition of perforin-dependent natural cytotoxicity through pentoxifylline does not result from changes in perforin production. Presumably, influence of PTX on natural cytotoxicity could be caused by e.g. interference with lymphocyte degranulation. Moreover, also other possibilities, such as PTX influence on conformational changes of perforin molecules and/or its influence on susceptibility of target cells to pore-forming of polyperforins cannot be excluded.