Regulation of ultraviolet radiation induced cutaneous photoimmunosuppression by toll-like receptor-4.

UVB radiation is a potent immunosuppressive agent that inhibits cell-mediated immune responses. The mechanisms by which UVB radiation influences cell-mediated immune responses have been the subject of extensive investigation. However, the role of innate immunity on photoimmunological processes has received little attention. The purpose of this study was to determine whether Toll-like receptor-4 (TLR4) contributed to UV-induced suppression of contact hypersensitivity (CHS) responses. TLR4⁻/⁻ and wild type C57BL/6 (TLR4+/+) mice were subjected to a local UVB immunosuppression regimen consisting of 100 mJ/cm² UVB radiation followed by sensitization with the hapten DNFB. Wild type TLR4+/+ mice exhibited significant suppression of contact hypersensitivity response, whereas TLR4⁻/⁻ developed significantly less suppression. The suppression in wild type TLR4+/+ mice could be adoptively transferred to naïve syngeneic recipients. Moreover, there were significantly fewer Foxp3 expressing CD4+CD25+ regulatory T-cells in the draining lymph nodes of UV-irradiated TLR4⁻/⁻ mice than TLR4+/+ mice. When cytokine levels were compared in these two strains after UVB exposure, T-cells from TLR4+/+ mice produced higher levels of IL-10 and TGF-ß and lower levels of IFN-γ and IL-17. Strategies to inhibit TLR4 may allow us to develop immunopreventive and immunotherapeutic approaches for management of UVB induced cutaneous immunosuppression.

Toll-like receptor-4 deficiency enhances repair of UVR-induced cutaneous DNA damage by nucleotide excision repair mechanism.

UVB-induced DNA damage has a critical role in the development of photoimmunosuppression. The purpose of this study was to determine whether repair of UVB-induced DNA damage is regulated by Toll-like receptor-4 (TLR4). When TLR4 gene knockout (TLR4(-/-)) and TLR4-competent (TLR4(+/+)) mice were subjected to 90 mJ cm(-2) UVB radiation locally, DNA damage in the form of cyclobutane pyrimidine dimers (CPDs) was repaired more efficiently in the skin and bone marrow-derived dendritic cells (BMDCs) of TLR4(-/-) mice in comparison to TLR4(+/+) mice. Expression of DNA repair gene XPA (xeroderma pigmentosum complementation group A) was significantly lower in skin and BMDCs of TLR4(+/+) mice than TLR4(-/-) mice after UVB exposure. When cytokine levels were compared in these strains after UVB exposure, BMDCs from UV-irradiated TLR4(-/-) mice produced significantly more interleukin (IL)-12 and IL-23 cytokines (P<0.05) than BMDCs from TLR4(+/+) mice. Addition of anti-IL-12 and anti-IL-23 antibodies to BMDCs of TLR4(-/-) mice (before UVB exposure) inhibited repair of CPDs, with a concomitant decrease in XPA expression. Addition of TLR4 agonist to TLR4(+/+) BMDC cultures decreased XPA expression and inhibited CPD repair. Thus, strategies to inhibit TLR4 may allow for immunopreventive and immunotherapeutic approaches for managing UVB-induced cutaneous DNA damage and skin cancer.