| Abstract: | Ultraviolet (UV) B irradiation of the skin induces acute inflammation, as characterized by erythema, edema, and immunosuppression, and is subsequently linked to the progression of skin cancer. Toll‐like receptor 4 (TLR4), a component of innate immunity, has been shown to play an important role in cancer. To elucidate the role of TLR4 in UVB‐induced tumor development, TLR4‐proficient (C3H/HeN) and TLR4‐deficient (C3H/HeJ) mice were exposed to multiple doses of UVB radiation (200 mJ/cm2) for 40 weeks. Photocarcinogenesis was retarded in terms of tumor incidence, and tumor latency, in mice deficient in TLR4 compared with TLR4‐proficient mice, whereas significantly greater numbers of tumors occurred in TLR4‐proficient mice. There was significant upregulation of inflammatory markers like COX‐2, PGE2, S100A8, and S100A9 in the skin of TLR4‐proficient mice than the skin of TLR4‐deficient mice. Furthermore, we found that TLR4‐proficient mice had a significantly higher number of Gr1+CD11b+ myeloid cells CD4+CD25+ regulatory T‐cells than TLR4‐deficient mice. Furthermore, the levels of interferon (IFN)‐γ cytokine was increased and the levels of interleukin (IL)‐4, IL‐10, and IL‐17 cytokines were decreased in serum, skin, and tumor lysates of TLR4‐deficient mice in comparison with samples from TLR4‐proficient mice. Together, our data indicate that TLR4‐mediated inflammation may cause suppression of antitumor responses and trigger the development of UVB‐induced skin cancers. Thus, strategies to inhibit TLR4‐mediated immune suppression may allow us to develop preventive and therapeutic approaches for the management of UVB‐induced cutaneous tumors. |
