Dexamethasone or cyclosporin A suppress mast cell-leukocyte cytokine cascades: Multiple mechanisms of inhibition of IgE- and mast cell-dependent cutaneous inflammation in the mouse 1

In allergic diseases, exposure of sensitized subjects to allergen induces the activation of tissue mast cells that results in an immediate-type hypersensitivity response and, in some individuals, a late phase response. We previously have reported that the neutrophil infiltration associated with IgE-dependent cutaneous inflammation in mice is mast cell-dependent and that TNF-α contributes significantly to this response. We report here that either dexamethasone or cyclosporin A can inhibit mouse mast cell TNF-α production in vitro, and that these agents also can significantly suppress the tissue swelling and leukocyte infiltration associated with two forms of TNF-α-associated inflammation in vivo: the entirely IgE- and mast cell-dependent inflammation at sites of passive cutaneous anaphylaxis reactions and the entirely TNF-α-dependent inflammation that is elicited by the direct intradermal injection of recombinant mouse TNF-α. Taken together, our in vitro and in vivo findings in mice indicate that dexamethasone or cyclosporin A can have at least three actions that interfere with the pathogenesis of IgE, mast cell-, and cytokine-dependent inflammatory reactions: suppression of the IgE-dependent increase in TNF-α mRNA by mast cells, inhibition of the IgE-dependent production of TNF-α protein by mast cells, and diminution of the responsiveness of target cells to TNF-α. Our findings in mice raise the possibility that similar actions of these agents in humans may account for some of the clinical efficacy of corticosteroids and cyclosporin A in allergic diseases.