513 the Toll Like Receptor-4 Antagonist, TAK-242, Enhances Repair of Ultraviolet Radiation-Induced DNA Damage and Inhibits UVB-induced Tumor Development in Mice

Ultraviolet (UV) irradiation of the skin induces acute inflammation, as characterized by erythema, edema, immunosuppression, and development of skin cancer. In addition, UVB induced DNA damage in the form of cyclobutane pyrimidine dimers (CPDs), can result in stable mutations. Toll-like receptor 4 (TLR4), a component of innate immunity, plays an important role in cancer. Previous studies from our laboratory indicate that UVB-induced DNA damage was greatly reduced in TLR4 deficient mice, indicated by significantly fewer CPD lesions in the skin of these mice. TLR4 deficient mice were also found to be resistant to UVB-induced immune suppression and carcinogenesis. In this study, we determined the efficacy of the TLR4 antagonist TAK-242 in regulation of UVB-induced DNA damage, inflammation and tumor development. Our results indicate that TAK-242 treatment increased the expression of the xeroderma pigmentosum group A (XPA) gene, resulting in repair of UVB-induced CPDs in the skin of SKH-1 mice. Treatment with TAK-242 also inhibited the activation of NLRP3 (p<0.05) in UVB-exposed skin of SKH-1 mice. When SKH-1 mice were exposed to multiple doses of UVB radiation (180 mJ/cm2) for 30 weeks, cutaneous carcinogenesis was significantly retarded (p<0.05) in mice treated with TAK-242 in comparison to vehicle treated mice. Pro-inflammatory cytokines like IL-1b, IL-6, and TNF-a were also found to be significantly upregulated (p<0.05) in vehicle treated mice than TAK-242 treated mice. Together, our data indicate that TLR4 inhibitor TAK-242 inhibits UVB induced DNA damage and inflammation, and prevents the development of UVB induced skin cancers in mice.