cis-urocanic acid induces mast cell degranulation and release of preformed TNF-alpha: A possible mechanism linking UVB and cis-urocanic acid to immunosuppression of contact hypersensitivity.
The search for effective inhibitors of transdermal drug-induced contact sensitization was directed to dermal mast-cell-degranulating agents (MCDA). Human skin organ cultures were employed to test whether cis-urocanic acid (C-UA) and other potential MCDAs cause mast cell degranulation. These were then tested for their ability to inhibit the induction phase of the contact hypersensitivity reaction (CHR). C-UA at 1 microg/ml significantly depleted mast cell chymase, whereas trans-urocanic acid (T-UA) was relatively ineffective. C-UA, but not T-UA, induced local effects of liberated mast cell TNF-alpha, as detected by E-selectin expression on the microvascular dermal endothelium. C-UA significantly reduced (>70%) the ear swelling response in Balb/c mice, when applied 24 h prior to application of a sensitizing amount of dinitrochlorobenzene (DNCB), and induced a prolonged (>3 weeks) state of immune tolerance (>40%). Similar effects on local immunosuppression of CHR were observed with topical chloroquine and capsaicin, while cromolyn, a mast cell membrane stabilizer, was unable to inhibit DNCB-induced CHR. It is suggested that MCDAs may interfere with downstream events associated with accessory cell function.
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D053818:Chymases; D004205:Cromolyn Sodium / Q000494:pharmacology; D003877:Dermatitis, Contact / Q000276:immunology* / Q000517:prevention & control; D004058:Diffusion; D004347:Drug Interactions; D019040:E-Selectin / Q000378:metabolism; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods; D007231:Infant, Newborn; D008407:Mast Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009924:Organ Culture Techniques; D012697:Serine Endopeptidases / Q000378:metabolism; D012879:Skin Physiological Phenomena / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014466:Ultraviolet Rays / Q000009:adverse effects*; D014560:Urocanic Acid / Q000494:pharmacology*