RELEASE OF BOTH PREFORMED AND NEWLY SYNTHESIZED TUMOR-NECROSIS-FACTOR-ALPHA (TNF-ALPHA)/CACHECTIN BY MOUSE MAST-CELLS STIMULATED VIA THE FC-EPSILON-RI - A MECHANISM FOR THE SUSTAINED ACTION OF MAST-CELL DERIVED TNF-ALPHA DURING IGE-DEPENDENT BIOLOGICAL RESPONSES

Mast cell-associated mediators are generally classified into two groups: the preformed mediators, which are stored in the cells' cytoplasmic granules and are released upon exocytosis, and the newly synthesized mediators, which are not stored but are produced and secreted only after appropriate stimulation of the cell. We now report that tumor necrosis factor-alpha (TNF-alpha)/cachectin represents a new type of mast cell-associated mediator, in that IgE-dependent mast cell activation results in the rapid release of preformed stores of the cytokine followed by the synthesis and sustained release of large quantities of newly formed TNF-alpha. We also demonstrate that challenge with specific antigen induces higher levels of TNF-alpha mRNA at skin sites sensitized with IgE in normal mice or mast cell-reconstituted genetically mast cell-deficient WBB6F1-W/W(nu) mice than at identically treated sites in WBB6F1-W/W(nu) mice that are devoid of mast cells. These findings identify mast cells as a biologically significant source of TNF-alpha/cachectin during IgE-dependent responses and define a mechanism whereby stimulation of mast cells via the FC-epsilon-RI can account for both the rapid and sustained release of this cytokine.