Ultraviolet B (UVB) light, a component of sunlight, is an important environmental cause of skin cancers in humans. The spectre of ozone depletion caused by environmental pollutants is upon us, raising the possibility that increasing amounts of UVB radiation will reach the surface of the earth. Under these circumstances, the potential exists in the near and distant future for higher frequencies of skin cancers, as well as other UVB-related diseases. In addition to its mutagenic effects, UVB radiation damages the cutaneous immune system, primarily by inducing the intracutaneous production or release of tumor necrosis factor-alpha (TNFalpha) which in turn impairs the induction of cell mediated immunity to antigens that gain access to, or arise within, the skin. In mice, as well as in humans, the UVB radiation induced impairment of contact hypersensitivity is not uniform in all individuals; some individuals are susceptible to the deleterious effects of UVB (UVB-susceptible - UVB-S) whereas others are resistant to UVB (UVB-resistant - UVB-R). Studies on inbred mouse strains revealed that the UVB-S and UVB-R phenotypes are genetically determined by alleles at the Tnfa and Lps loci. These findings have led to the central hypothesis upon which this grant application is based: Polymorphism within the 5' untranslated region of the mouse Tnfa loci is responsible for the differential responsiveness to UVB radiation such that the Tnfa alleles of UVB-S individuals transcribe and/or translate excessive amounts of TNFalpha. A subsidiary hypothesis postulates that TNFalpha is produced intracutaneously by the keratinocytes in response to UVB radiation, and that trans-urocanic acid, which is racemized within keratinocytes by UVB radiation to cis-urocanic acid, is the photoreceptor on which UVB radiation acts to initiate Tnfa transcription and/or translation. To test these hypotheses we plan to: 1. Describe the extent of polymorphisms at the mouse Tnfa locus by cloning and sequencing; determine transcriptional efficiency of different Tnfa alleles, and identify intracutaneous sources of Tnfa mRNA; 2. Analyze the molecular basis of transcriptional and/or translational differences among polymorphic mouse Tnfa alleles by identifying nuclear binding factors and by determining the role of the urocanic acid in this process. Understanding the link between Tnfa polymorphisms and UVB susceptibility will be important, not only in the context of ozone depletion and rising incidence of sunlight-induced skin cancers, but also in relation to susceptibility to cutaneous pathogens responsible for morbidity and mortality through TNFalpha-dependent immunopathogenic processes.
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