Polymorphisms in the TNF region confer susceptibility to UVB-induced impairment of contact hypersensitivity induction in mice and humans.
Acute, low-dose ultraviolet B radiation protocols impair induction of contact hypersensitivity (CHS) to highly reactive haptens in some mice and humans (UVB-susceptible) but not others (UVB-resistant). These deleterious effects of ultraviolet radiation appear to be mediated in part by tumour necrosis factor alpha (TNF-alpha), which is released from, or accumulates in, UVB-exposed skin. To test the hypothesis that a polymorphism of the Tnfa locus governs the UVB-S and UVB-R phenotypes, studies have been conducted in genetically disparate strains of mice. Mice carrying the Tnf(d) allele [with precisely 14 (CA) repeats in the promoter region] display the UVB-R phenotype, whereas mice with different Tnf alleles [with (CA) repeats of </>14] display the UVB-S phenotype. Molecular genetic studies of the TNF region of HLA in humans displaying either the UVB-S or UVB-R phenotype reveal a significant increase in the frequencies of TNFa2 in UVB-S individuals (P=0.00032) and of TNFd3 in UVB-R individuals (P=0.012). Moreover, DNA sequencing analyses of five single-nucleotide polymorphisms (SNPs) of the TNF promoter region revealed a significant increase in the frequency of TNF/-863A (P=0.015). We propose that the TNF region dictates susceptibility to the deleterious effects of UVB radiation on the induction of contact hypersensitivity in both mice and humans, and that the UVB-S-promoting polymorphisms significantly promote the risk of sunlight-induced skin cancer in humans.
Niizeki
Hironori
H
Department of Dermatology and Clinical Research Institute, National Tokyo Medical Center, 2-5-1 Higashi-ga-oka, Meguro, Tokyo, Japan. hniizeki@ntmc.hosp.go.jp
Inoko
Hidetoshi
H
Wayne Streilein
J
J
D000818:Animals; D003877:Dermatitis, Contact / Q000517:prevention & control*; D029721:Drosophila Proteins; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D018895:Microsatellite Repeats; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011836:Radiation Tolerance; D011956:Receptors, Cell Surface / Q000235:genetics; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D014466:Ultraviolet Rays
D029721:Drosophila Proteins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha