Thymidine dinucleotides inhibit contact hypersensitivity and activate the gene for tumor necrosis factor α

DNA is a target for ultraviolet-B-induced inhibition of contact hypersensitivity, and small DNA fragments such as thymidine dinucleotides (pTpT) can simulate several ultraviolet-induced effects. To determine whether pTpT mimics the suppressive influence of ultraviolet-B on contact hypersensitivity, we compared the effects of topical application of pTpT with those of ultraviolet-B irradiation on C57BL/6 mice sensitized to dinitrofluorobenzene. Mice pretreated with pTpT or ultraviolet-B irradiation showed markedly suppressed ear swelling responses to dinitrofluorobenzene challenge. Because tumor necrosis factor a mediates ultraviolet-B-induced suppression of contact hypersensitivity, and because pTpT exerts many ultraviolet-mimetic effects by augmenting mRNA and protein levels of effector molecules, we asked if pTpT mimics ultraviolet-B's upregulatory influence on tumor necrosis factor a expression. Using transgenic mice carrying a chloramphenicol acetyl transferase reporter linked to the tumor necrosis factor a promoter, we examined effects of ultraviolet-B irradiation versus intradermal injection of pTpT on tumor necrosis factor a gene transcription. Both treatments induced cutaneous chloramphenicol acetyl transferase activity. Ultraviolet-B or pTpT treatment of cultured dermal fibroblasts from these mice also stimulated chloramphenicol acetyl transferase activity. To determine whether human cells responded similarly, a well-differentiated ultraviolet-responsive human squamous cell carcinoma line was treated with pTpT. pTpT increased tumor necrosis factor a mRNA expression and protein secretion in a dose-dependent manner. Our findings expand the spectrum of ultraviolet effects mimicked by pTpT to include inhibition of contact hypersensitivity and activation of the tumor necrosis factor a gene. These results support the hypothesis that DNA photoproducts and/or their repair intermediates trigger many of the biologic consequences of ultraviolet irradiation.