PRODUCTION OF PROINFLAMMATORY CYTOKINES AND CYTOKINES INVOLVED IN THETH1 TH2 BALANCE IS MODULATED BY PENTOXIFYLLINE/

The modulation of cytokine release induced by pentoxifylline (PTX) has recently been demonstrated not to be restricted solely to tumor necro sis factor (TNF)-alpha. This prompted us to study the influence of PTX on a larger spectrum of cytokines with proinflammatory actions [TNF-a lpha, interleukin-6, (IL)-6, IL-1 beta, IL-8] or with implied actions in the TH1 (IL-2, IFN-gamma)/TH2 (IL-10) balance. The IL-1RA was also explored. This work was performed using a whole-blood model in which c ytokine production is measured after stimulation by lipopolysaccharide (LPS) (25 mu g/ml) and phytohemagglutinin (PHA) (5 mu g/ml) in 1:10 d iluted whole blood. The stimulation test was performed in blood from h ealthy controls and from septic patients (without septic shock) in the presence or absence of PTX at 10(-6), 10(-5), 10(-4), or 10(-3) M. In controls and septic patients, at a 10(-4) M PTX concentration the pro duction of IL-2 is strongly diminished (26-32% of the basal level), fo llowed by diminution of IFN-gamma (30-40%). As expected, of the proinf lammatory cytokines TNF was the most strongly suppressed (50% of basel ine) followed by IL-1 (about 80% of basal production). Finally, IL-10 was also influenced by PTX (65% of baseline). At 10(-4) M, IL-1RA and IL-6 were unaffected by PTX. Taken altogether, our data demonstrate th at PTX possesses a much broader spectrum of activity on cytokine produ ction than was initially described, and it appears to be a potential a nd promising immunotherapeutic agent.