Differential effects of pentoxifylline, a non-specific phosphodiesterase inhibitor, on the production of IL-10, IL-12 p40 and p35 subunits by murine peritoneal macrophages

Pentoxifylline (PTX), a methylxanthine derivative, has been reported to be an effective drug in inhibiting TNF-alpha responses during septic shock. Th e inhibition of TNF-alpha production seems to be correlated with increased intracellular cAMP levels. PTX also affects the production of other cytokin es such as IL-1, IL-6, IL-10, IL-12, and IFN-gamma. However, inhibition, as well as enhancement of cytokine production, has been observed in vitro, de pending on the PTX concentration and cell type used. IL-12 is a heterodimeric cytokine that plays an important role in the devel opment of Th1-mediated inflammatory responses. IL-12 along with TNF-alpha a nd other proinflammatory cytokines has shown to be responsible for the path ological reaction, which may lead to septic shuck. For biological activity, the expression of both subunits of IL-12, p35 and p40, is required. Moreov er, the p40 chain of IL-12 specifically inhibits the effects of the IL-12 h eterodimer. In this study, we investigated the effects of PTX on the production of both proinflammatory (TNF-alpha, IL-6, IL-12) and anti-inflammatory (IL-10) cyt okines by murine macrophages (M phi). We have found that PTX, at concentrat ions below 100 mu g/ml, selectively inhibited the production of TNF-alpha. Forskolin, a cAMP-elevating agent, similarly affected the production of the cytokines tested. However, at higher concentrations, PTX inhibited the pro duction of TNF-alpha, IL-10, and IL-12 p35, but surprisingly, PTX enhanced the production of IL-12 p40, Concentrations of IL-10 were negatively correl ated with the concentrations of IL-12 p40 subunit, These results further co nfirm the relevance of the use of PTX in clinical trials of immunological d isorders characterised by inappropriate Th1 type immune responses. (C) 2000 Elsevier Science B.V. All rights reserved.