THE REGULATION OF TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION IN MURINE MAST-CELLS - PENTOXIFYLLINE OR DEXAMETHASONE INHIBITS IGE-DEPENDENT PRODUCTION OF TNF-ALPHA BY DISTINCT MECHANISMS

Mast cells activated via high-affinity receptors for IgE can produce a variety of multifunctional cytokines, including TNF-alpha, which is t hought to be involved in the pathophysiology of allergic diseases and other inflammatory disorders, We investigated the regulation of Fc(eps ilon)RI-dependent TNF-alpha production by mouse mast cells using dexam ethasone and pentoxifylline, pharmacological agents which are known to suppress TNF-alpha production by macrophages. We now report that eith er dexamethasone or pentoxifylline can inhibit IgE-dependent mouse mas t cell production of TNF-alpha; however, the major site of action of t hese agents was different. Pentoxifylline inhibited mast cell TNF-alph a gene transcription, while dexamethasone inhibited TNF-alpha producti on predominantly by a posttranscriptional mechanism. These results dem onstrate that the synthesis of mast cell TNF-alpha can be regulated ph armacologically at either the transcriptional or the translational lev el and that pentoxifylline and dexamethasone, two agents that are used to treat inflammatory disorders, can modulate mast cell TNF-alpha pro duction at different points in the synthetic pathway of this cytokine. (C) 1996 Academic Press, Inc.