Pentoxifylline exerts synergistic immunomodulatory effects in combination with dexamethasone or cyclosporin A

The methylxanthine derivative pentoxifylline (PTX) is an immunomodulatory agent with incompletely characterized effects on cytokine production. To analyse these effects and to delineate new combination strategies in immunotherapy, we have investigated immunomodulatory properties of PTX in combination with dexamethasone (DEX) or cyclosporin A (CsA). Stimulated human peripheral blood mononuclear cells were treated with clinically relevant concentrations of PTX (12.5-100 mu g/ml), DEX (0.01-10 mu M) or CsA (12.5-50 ng/ml), alone or in combination. With increasing doses of PTX the maximum supernatant titres of tumour necrosis factor (TNF)-alpha, interleukin (IL)-2 and interferon (IFN)-gamma decreased concomitantly, and all cultures co-treated with DEX showed synergism. Release of IL-6 was not consistently altered under PTX treatment. Similarly, PTX and CsA synergistically inhibited the release of IL-2, IFN-gamma and, to a lesser degree, TNF-alpha. Although PTX alone did not significantly reduce lymphoproliferation, both combinations of drugs synergistically inhibited this process. Furthermore, to demonstrate that the key mechanism of PTX-induced effects is an increase in intracellular cyclic adenosine 3':5'-monophosphate (cAMP) levels, identical experiments were performed using dibutyryl-cAMP instead of PTX. In cultures treated with PTX and DEX, expression of different cell receptors was analysed. Expression of IL-2 receptor (IL-2R) was reduced in cultures treated with PTX, and combination with DEX led to further reduction. Expression of intercellular adhesion molecule (ICAM)-1 and of leucocyte function antigen (LFA)-1 alpha was also synergistically reduced, though to a lesser degree. HLA-DR expression remained unchanged. In conclusion, we demonstrate that clinically relevant levels of PTX exert profound immunomodulatory effects in vitro, and that the combined treatment with DEX or CsA has synergistic effects.