cis-urocanic acid suppression of contact hypersensitivity induction is mediated via tumor necrosis factor-alpha.

Abstract

Ultraviolet B (UVB) light impairs the induction of contact hypersensitivity to epicutaneously applied haptens in certain strains of mice by a genetically determined mechanism that depends upon the participation of TNF-alpha. Because the superficial epidermis contains large amounts of trans-urocanic acid (trans-UCA), because exposure to UVB radiation converts this compound to cis-UCA, and because cis-UCA has been reported to be immunosuppressive, we have examined the possibility that the TNF-alpha-dependent effects of UVB on contact hypersensitivity induction in mice are mediated via conversion of trans- to cis-UCA. By injecting cis-UCA intradermally before application of dinitrofluorobenzene, by treating cis-UCA-injected mice systemically with neutralizing anti-TNF-alpha antibodies, and by comparing the consequences of these maneuvers in UVB-susceptible and UVB-resistant strains of mice, we have determined a) that cis-UCA can impair the induction of contact hypersensitivity in a manner similar to UVB radiation, and that the impairment is dependent upon TNF-alpha; b) that cis-UCA altered the morphology of epidermal Langerhans cells in a manner similar to UVB radiation, and that the alteration was dependent, in part, upon TNF-alpha; and c) that the inhibitory effects of cis-UCA on induction of contact hypersensitivity and the histologic effects of this compound on epidermal Langerhans cells appear to be influenced by alleles at the Tnf alpha and Lps loci. Based on these findings we propose that UVB radiation impairs the induction of contact hypersensitivity in mice by converting trans-urocanic acid to cis-UCA within the epidermis; cis-UCA in turn causes the local release of TNF-alpha, which thwarts sensitization by its ability to trap epidermal Langerhans cells transiently within the epidermis, and thereby prevents the immunogenic signal from reaching the draining lymph node where activation of unprimed, Ag-specific T cells must occur.