ABSTRACT
The cellular and molecular mechanisms by which UV radiation modulates inflammation and immunity while simultaneously maintaining skin homeostasis is complex and not completely understood. Similar to the effects of UV, IL-33 has potent immune-modulating properties that are mediated by the downstream induction of cytokines and chemokines. We have discovered that exposure of mice in vivo or human skin samples ex vivo to inflammatory doses of UVB induced IL-33 expression within the epidermal and dermal skin layers. Using a combination of murine cell lines and primary human cells, we demonstrate that both UV and the oxidized lipid platelet activating factor induce IL-33 expression in keratinocytes and dermal fibroblasts. Highlighting the significance of these results, we found that administering IL-33 to mice in vivo suppressed the induction of Th1-mediated contact hypersensitivity responses. This may have consequences for skin cancer growth because UV-induced squamous cell carcinomas that evade immunological destruction were found to express significantly higher levels of IL-33. Finally, we demonstrate that dermal mast cells and skin-infiltrating neutrophils closely associate with UV-induced IL-33-expressing fibroblasts. Our results therefore identify and support a role for IL-33 as an important early danger signal produced in response to inflammation-inducing UV radiation.
Subject(s)
Carcinoma, Squamous Cell/etiology , Inflammation/etiology , Interleukins/metabolism , Skin Neoplasms/etiology , Skin/radiation effects , Ultraviolet Rays/adverse effects , Adult , Animals , Blotting, Western , Carcinoma, Squamous Cell/pathology , Female , Fibroblasts/immunology , Fibroblasts/metabolism , Fibroblasts/radiation effects , Fluorescent Antibody Technique , Humans , Inflammation/pathology , Interleukin-33 , Keratinocytes/immunology , Keratinocytes/metabolism , Keratinocytes/radiation effects , Mast Cells/immunology , Mast Cells/metabolism , Mast Cells/radiation effects , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Neutrophils/immunology , Neutrophils/metabolism , Neutrophils/radiation effects , Platelet Activating Factor/metabolism , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , Skin/immunology , Skin/metabolism , Skin Neoplasms/pathologyABSTRACT
Contact hypersensitivity is a T-cell-mediated response to a hapten. Exposing C57BL/6 mice to UV B radiation systemically suppresses both primary and secondary contact hypersensitivity responses. The effects of UVB on in vivo T-cell responses during UVB-induced immunosuppression are unknown. We show here that UVB exposure, before contact sensitization, inhibits the expansion of effector CD4+ and CD8+ T cells in skin-draining lymph nodes and reduces the number of CD4+ and IFN-gamma+ CD8+ T cells infiltrating challenged ear skin. In the absence of UVB, at 10 weeks after initial hapten exposure, the ear skin of sensitized mice was infiltrated by dermal effector memory CD8+ T cells at the site of challenge. However, if mice were previously exposed to UVB, this cell population was absent, suggesting an impaired development of peripheral memory T cells. This finding occurred in the absence of UVB-induced regulatory CD4+ T cells and did not involve prostaglandin E2, suggesting that the importance of these two factors in mediating or initiating UVB-induced immunosuppression is dependent on UVB dose. Together these data indicate that in vivo T-cell responses are prone to immunoregulation by UVB, including a novel effect on both the activated T-cell pool size and the development of memory T cells in peripheral compartments.
