Regulatory effects of pentoxifylline on T-helper cell-derived cytokine production in human blood cells

Pentoxifylline (PTX), a methyl xanthine derivative, was examined for its regulatory effect on Th1- and Th2-cell-derived cytokines in human whole blood and peripheral blood mononuclear cells stimulated with phytohemagglutinin (PHA) and phorbol myristate acetate (PMA). Cytokine production was analyzed by enzyme-linked immunosorbent assay and cytokine mRNA expression was examined by the polymerase chain reaction (PCR) after reverse transcription (RT). The results showed that PTX at 5 x 10(-4) M concentration selectively suppressed Th-1 cytokines [interleukin-2 (IL-2) and interferon-gamma (IFN-gamma)] but not IL-4, as observed by the measurement of protein secretion. Using sensitive RT-PCR assays, data show that at this same PTX concentration (5 x 10(-4) M), these cells also exhibited inhibition in the expression of IL-4 and IL-10 mRNA, together with inhibition of IL-2 and IFN-gamma mRNA expression. At 1 x 10(-4) M, no apparent change in IL-4 and IL-10 mRNA expression was observed, whereas IL-2 mRNA was still inhibited. It was noted that PTX at 1 x 10(-3) M induced a generalized inhibition of all cytokines. Our findings showed that PTX at the appropriate concentrations could induce selective suppression of IL-2 and IFN-gamma, whereas at high concentrations this drug could act as a suppressive agent of both Th1- and Th2-derived cytokines. Moreover, these data provide further evidence that the induction of IL-2 gene transcription is highly sensitive to an elevation of cAMP, whereas IL-4 gene transcription appeared to be less affected.