Pentoxifylline inhibits the synthesis and IFN-gamma-inducing activity of IL-18

The effect of phosphodiesterase-inhibiting anti-inflammatory drug pentoxify lline (PTX) on LPS-induced IL-18 synthesis and IL-18-mediated IFN-gamma -in duction were investigated. In a dose-dependent manner PTX inhibited product ion of IL-18 in LPS-treated cultures of murine spleen cells and bone marrow -derived macrophages. Similarly, PTX treatment significantly reduced blood IL-18 levels and expression of spleen IL-18 mRNA in LPS-challenged mice. Th e inhibitory effect of PTX was specific for IL-18, since LPS-induced IL-12 p40 release was not suppressed either in splenocyte cultures or blood of LP S-injected animals. Synergistic induction of IFN-gamma by combined IL-12/IL -18 treatment was also inhibited by PTX in vitro and in vivo. Experiments w ith IL-12 pretreatment of splenocytes, followed by IL-18 stimulation, revea led that PTX suppressed both IL-12 and IL-18 signals responsible for IFN-ga mma induction. These results suggest that interference with IL-18 synthesis and IFN-gamma -inducing activity might contribute to anti-inflammatory act ions of PTX.