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