DEXAMETHASONE OR CYCLOSPORINE-A SUPPRESS MAST CELL-LEUKOCYTE CYTOKINECASCADES - MULTIPLE MECHANISMS OF INHIBITION OF IGE-DEPENDENT AND MAST-CELL-DEPENDENT CUTANEOUS INFLAMMATION IN THE MOUSE

In allergic diseases, exposure of sensitized subjects to allergen indu ces the activation of tissue mast cells that results in an immediate-t ype hypersensitivity response and, in some individuals, a late phase r esponse. We previously have reported that the neutrophil infiltration associated with IgE-dependent cutaneous inflammation in mice is mast c ell-dependent and that TNF-alpha contributes significantly to this res ponse. We report here that either dexamethasone or cyclosporin A can i nhibit mouse mast cell TNF-alpha production in vitro, and that these a gents also can significantly suppress the tissue swelling and leukocyt e infiltration associated with two forms of TNF-alpha-associated infla mmation in vivo: the entirely IgE- and mast cell-dependent inflammatio n at sites of passive cutaneous anaphylaxis reactions and the entirely TNF-alpha-dependent inflammation that is elicited by the direct intra dermal injection of recombinant mouse TNF-alpha. Taken together, our i n vitro and in vivo findings in mice indicate that dexamethasone or cy closporin A can have at least three actions that interfere with the pa thogenesis of IgE, mast cell-, and cytokine-dependent inflammatory rea ctions: suppression of the IgE-dependent increase in TNF-alpha mRNA by mast cells, inhibition of the IgE-dependent production of TNF-alpha p rotein by mast cells, and diminution of the responsiveness of target c ells to TNF-alpha. Our findings in mice raise the possibility that sim ilar actions of these agents in humans may account for some of the cli nical efficacy of corticosteroids and cyclosporin A in allergic diseas es.