Abstract 525: Toll-like receptor-4 mediated cutaneous immune responses augment ultraviolet radiation-induced DNA damage and tumor development

Abstract

Abstract UV (ultraviolet) B induced DNA damage plays a critical role in development of skin cancer. The molecular basis for this biologic activity resides at least in part from the demonstrated ability of this form of radiant energy to damage DNA, predominantly in the form of cyclobutane pyrimidine dimers (CPD). The purpose of this study was to determine whether toll-like receptor-4 (TLR4) contributed to UV-induced DNA damage responses and cutaneous tumor development. TLR4 deficient and wild type (WT) mice were subjected to a local UVB induced DNA damage regimen consisting of 90 mJ/cm2 UVB radiation. Wild type mice exhibited significant (p<0.05) DNA damage in the form of cyclobutane pyrimidine dimers (CPD), whereas TLR4 deficient mice developed significantly fewer CPD (p<0.05) in their skin and bone marrow dendritic cells (BMDC). The expression of DNA repair gene XPA was significantly less (p<0.05) in skin and BMDC from WT mice than TLR4 deficient mice after UVB exposure. When cytokine levels were compared in these two strains after UVB exposure, BMDC from UV-irradiated TLR4 deficient mice produced significantly more IL-12 and IL-23 cytokines (p<0.05) than BMDC from WT mice. Furthermore, we found that Toll like receptor-4 (TLR4) promoted UVB induced tumor development. We observed that UVB induced skin carcinogenesis was retarded in terms of tumor incidence, and tumor latency, in mice deficient in TLR4 compared to WT mice, whereas significantly greater (p<0.05) numbers of tumors occurred in WT mice. Further, we found that tumor-bearing WT mice produced more IL-17 and IL-10 (p<0.05), whereas TLR4 deficient mice produced more IFN-γ (p<0.05). CD4+CD25+ regulatory T-cells from WT mice produced more IL-10 (p<0.05) than regulatory T-cells from TLR4 deficient mice. There was a significant increase (p<0.05) in Foxp3 expression in skin of WT mice than TLR4 deficient mice. Thus, strategies to inhibit TLR4 may allow us to develop immunopreventive and immunotherapeutic approaches for management of UVB induced cutaneous DNA damage and skin cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 525. doi:1538-7445.AM2012-525