The inhibition of antigen-presenting activity of dendritic cells resulting from UV irradiation of murine skin is restored byin vitrophotorepair of cyclobutane pyrimidine dimers

Abstract

Exposing skin to UVB (280-320 nm) radiation suppresses contact hypersensitivity by a mechanism that involves an alteration in the activity of cutaneous antigenpresenting cells (APC). UV-induced DNA damage appears to be an important molecular trigger for this effect. The specific target cells in the skin that sustain DNA damage relevant to the immunosuppressive effect have yet to be identified. We tested the hypothesis that UV-induced DNA damage in the cutaneous APC was responsible for their impaired ability to present antigen after in vivo UV irradiation. Cutaneous APC were collected from the draining lymph nodes of UVBirradiated, hapten-sensitized mice and incubated in vitro with liposomes containing a photolyase (Photosomes; Applied Genetics, Freeport, NY), which, upon absorption of photoreactivating light, splits UV-induced cyclobutane pyrimidine dimers. Photosome treatment followed by photoreactivating light reduced the number of dimer-containing APC, restored the in vivo antigen-presenting activity of the draining lymph node cells, and blocked the induction of suppressor T cells. Neither Photosomes nor photoreactivating light alone, nor photoreactivating light given before Photosomes, restored APC activity, and Photosome treatment did not reverse the impairment of APC function when isopsoralen plus UVA (320-400 nm) radiation was used instead of UVB. These controls indicate that the restoration of APC function matched the requirements of Photosome-mediated DNA repair for dimers and post-treatment photoreactivating light. These results provide compelling evidence that it is UVinduced DNA damage in cutaneous APC that leads to reduced immune function.Exposing skin to UV radiation induces lesions in cellular DNA. Among those lesions, cyclobutane pyrimidine dimers (subsequently referred to as ''dimers'') and photoproducts predominate and are believed to play an important role in initiating skin cancer (1). UV irradiation of murine skin also reduces certain immune responses, and this suppressed immunity plays a significant role in UV carcinogenesis by allowing highly antigenic, UV-induced skin cancers to grow unimpeded (2, 3). The mechanisms of UVB (280-320 nm)-induced immune suppression are not completely understood; evidence is accumulating, however, that the induction of dimers by UVB represents a key step in the initiation of immune suppression (4-6), although other mechanisms such as the photoisomerization of urocanic acid (7), free-radical formation (8), and signal transduction-mediated activation of transcription factors (9, 10) may play a role as well.Immunological changes induced by UVB can be manifested locally within the UV-irradiated skin or systemically at sites distant from the UV-irradiated skin, depending on the experimental conditions (11). A well studied, local immunological effect of UV irradiation is inhibition of the contact hypersensitivity (CHS) response, which occurs after a contact sensitizer is applied to UV-irradiated skin of certain strains of mice (reviewed in ref. 12). The CH...

A Role for Inflammatory Mediators in the Induction of Immunoregulatory B Cells

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Extracorporeal photopheresis in chronic graft-versus-host disease

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Suppression of UVB-induced phosphorylation of mitogen-activated protein kinases and nuclear factor kappa B by green tea polyphenol in SKH-1 hairless mice

“…The incidence of nonmelanoma skin cancer, comprising of basal-and squamous-cell carcinoma, continues to increase in the United States, and solar UV, particularly its UVB (280-320 nm) spectrum, is the primary cause of these cancers and other cutaneous pathologies in the human population, more so in Caucasian individuals (Mukhtar and Elmets, 1996;Ananthaswamy et al, 1997;Greenlee et al, 2000;Jemal et al, 2000;de Gruijl, 2002). Exposure of mammalian skin to UV radiation alter cellular function via DNA damage (Vink et al, 1997;Katiyar et al, 2000), generation of reactive oxygen species (ROS) (Scharffetter-Kochanek et al, 1997;Katiyar et al, 2001a, b), activation and phosphorylation of mitogen-activated protein kinases (MAPKs), nuclear factor kappa B (NF-kB), and other signaling events (Iordanov et al, 1997;Chen et al, 1999;Katiyar and Mukhtar, 2001;Lefort et al, 2001;Bachelor et al, 2002;Hildesheim et al, 2002;Afaq et al, 2003a), and acts both as a tumor initiator and tumor promoter in animal models (Gensler and Welch, 1992;Katiyar et al, 1997). The UVB-induced activation of signal transduction pathways that control the expression of genes is responsible for its tumor-promoting effects (Huang et al, 1996;Chen et al, 1998).…”