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.
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 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-alpha contributes significantly to this response. We report here that either dexamethasone or cyclosporin A can inhibit mouse mast cell TNF-alpha production in vitro, and that these agents also can significantly suppress the tissue swelling and leukocyte infiltration associated with two forms of TNF-alpha-associated inflammation in vivo: the entirely IgE- and mast cell-dependent inflammation at sites of passive cutaneous anaphylaxis reactions and the entirely TNF-alpha-dependent inflammation that is elicited by the direct intradermal injection of recombinant mouse TNF-alpha. 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-alpha mRNA by mast cells, inhibition of the IgE-dependent production of TNF-alpha protein by mast cells, and diminution of the responsiveness of target cells to TNF-alpha. 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.
Wershil
B K
BK
Combined Program in Pediatric Gastroenterology, Children's Hospital, Boston.
Furuta
G T
GT
Lavigne
J A
JA
Choudhury
A R
AR
Wang
Z S
ZS
Galli
S J
SJ
D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D007073:Immunoglobulin E / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D009504:Neutrophils / Q000187:drug effects*; D012867:Skin / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D014409:Tumor Necrosis Factor-alpha; D007073:Immunoglobulin E; D003907:Dexamethasone; D016572:Cyclosporine