Inhibition of human interleukin‐12 production by pentoxifylline

Abstract

Pharmacological control of interleukin‐12 (IL‐12) production may be a key therapeutic strategy for modulating immunological diseases dominated by type‐1 cytokine responses. In this study, we investigated the effects of pentoxifylline on the production of IL‐12 by human blood mononuclear cells and primary human monocytes stimulated with heat‐killed Staphylococcus aureus Cowan strain I (SAC) or lipopolysaccharide (LPS). Pentoxifylline potently suppressed production of IL‐12 in a concentration‐dependent manner. In these same experiments, tumour necrosis factor‐α (TNF‐α) production was inhibited and IL‐10 and prostaglandin E₂ (PGE₂) production was enhanced by treatment with pentoxifylline. Suppression of IL‐12 production by pentoxifylline was found to be independent of several known endogenous inhibitors of IL‐12, such as IL‐10, transforming growth factor‐β (TGF‐β), IL‐4 and PGE₂. RNase protection assays revealed that pentoxifylline inhibited accumulation of both IL‐12 p40 and p35 mRNA, suggesting a predominant mRNA locus for pentoxifylline‐induced IL‐12 inhibition. Low levels of pentoxifylline added to the suppression of IL‐12 production by suboptimal inhibiting doses of dexamethasone, suggesting that this drug combination may have therapeutic utility. These results provide a firm rationale for the use of pentoxifylline in clinical trials of immunological disorders characterized by inappropriate type‐1 immune responses.