The Regulation of Tumor Necrosis Factor-α Production in Murine Mast Cells: Pentoxifylline or Dexamethasone Inhibits IgE-Dependent Production of TNF-α by Distinct Mechanisms

Mast cells activated via high-affinity receptors for IgE can produce a variety of multifunctional cytokines, including TNF-α, which is thought to be involved in the pathophysiology of allergic diseases and other inflammatory disorders. We investigated the regulation of FcϵRI-dependent TNF-α production by mouse mast cells using dexamethasone and pentoxifylline, pharmacological agents which are known to suppress TNF-α production by macrophages. We now report that either dexamethasone or pentoxifylline can inhibit IgE-dependent mouse mast cell production of TNF-α; however, the major site of action of these agents was different. Pentoxifylline inhibited mast cell TNF-α gene transcription, while dexamethasone inhibited TNF-α production predominantly by a posttranscriptional mechanism. These results demonstrate that the synthesis of mast cell TNF-α can be regulated pharmacologically at either the transcriptional or the translational level and that pentoxifylline and dexamethasone, two agents that are used to treat inflammatory disorders, can modulate mast cell TNF-α production at different points in the synthetic pathway of this cytokine.