Ultraviolet (UV) radiation plays a critical role in the induction of nonmelanoma skin cancer. UV radiation is also immune suppressive, and the immune suppression induced by UV irradiation has been identified as a major risk factor for skin cancer induction. Previously, we showed that UV exposure activates a cytokine cascade involving prostaglandin (PG)E2, interleukin (IL)-4, and IL-10 that induces immune suppression. However, the earliest molecular events that occur immediately after UV exposure, especially those upstream of PGE2, are not well defined. UV-irradiated keratinocytes secrete the inflammatory phospholipid mediator, platelet-activating factor (PAF). Because PAF upregulates the production of immunomodulatory compounds, including PGE2, we tested the hypothesis that UV-induced PAF activates cytokine production and initiates UV-induced immune suppression. Both UV and PAF activated cyclooxygenase (COX)-2 and IL-10 reporter gene construct transcription. PAF mimicked the effects of UV in vivo and suppressed delayed-type hypersensitivity (DTH). Furthermore, immune suppression was blocked when UV-irradiated mice were injected with PAF receptor antagonists. In addition to the well-known role of PAF as a proinflammatory lipid mediator, we propose that the PAF receptor senses cellular damage through the recognition of PAF and/or PAF-like molecules, such as oxidized phosphatidylcholine, which activates cytokine transcription and induces systemic immune suppression.

Ultraviolet (UV) radiation is carcinogenic and immunosuppressive. UV-induced immune suppression is mediated by antigen-specific T cells, which can transfer suppression to normal recipients. These cells are essential for controlling skin cancer development in the UV-irradiated host and in suppressing other immune responses, such as delayed-type hypersensitivity. Despite their importance in skin cancer development, their exact identity has remained elusive. We show here that natural killer T cells from UV-irradiated donor mice function as suppressor T cells and play a critical role in regulating the growth of UV-induced skin cancers and suppressing adaptive immune responses in vivo.

Exposure to UV radiation induces skin cancer and suppresses the immune response. To induce immune suppression, the electromagnetic energy of UV radiation must be absorbed by an epidermal photoreceptor and converted into a biologically recognizable signal. Two photoreceptors have been recognized: DNA and transurocanic acid (UCA). Trans-UCA is normally found in the outermost layer of skin and isomerizes to the cis isomer upon exposure to UV radiation. Although UCA was identified as a UV photoreceptor years ago, and many have documented its ability to induce immune suppression, its exact mode of action remains elusive. Particularly vexing has been the identity of the molecular pathway by which cis-UCA mediates immune suppression. Here we provide evidence that cis-UCA binds to the serotonin immune regulation ͉ inflammation ͉ serotonin ͉ UV radiation

Psoralen plus UVA (PUVA) is used as a very effective treatment modality for various diseases, including psoriasis and cutaneous T-cell lymphoma. PUVA-induced immune suppression and/or apoptosis are thought to be responsible for the therapeutic action. However, the molecular mechanisms by which PUVA acts are not well understood. We have previously identified platelet-activating factor (PAF), a potent phospholipid mediator, as a crucial substance triggering ultraviolet B radiation-induced immune suppression. In this study, we used PAF receptor knockout mice, a selective PAF receptor antagonist, a COX-2 inhibitor (presumably blocking downstream effects of PAF), and PAF-like molecules to test the role of PAF receptor binding in PUVA treatment. We found that activation of the PAF pathway is crucial for PUVAinduced immune suppression (as measured by suppression of delayed type hypersensitivity to Candida albicans) and that it plays a role in skin inflammation and apoptosis. Psoralen and UVA (PUVA) photochemotherapy consists of the topical or oral application of a photosensitizing psoralen (ie, a furocoumarin compound), such as 8-methoxypsoralen, followed by exposure to photoactivating UVA light.

The ultraviolet radiation present in sunlight is the primary cause of nonmelanoma skin cancer and has been implicated in the development of cutaneous malignant melanoma. In addition, ultraviolet is immune suppressive and the suppression induced by ultraviolet radiation has been identified as a risk factor for skin cancer induction. Ultraviolet also suppresses the immune response to infectious agents. In most experimental models, ultraviolet is applied to immunologically naive animals prior to immunization. Of equal concern, however, is the ability of sunlight to suppress established immune reactions, such as the recall reaction in humans, which protects against microbial infections. Here we demonstrate that solar-simulated ultraviolet radiation, applied after immunization, suppresses immunologic memory and the elicitation of delayed-type hypersensitivity. Further, we found that wavelengths in the ultraviolet A region of the solar spectrum were critical for inducing immune suppression. Ultraviolet A (320-400 nm) radiation was as effective as solar-simulated ultraviolet A + B (290-400 nm) in suppressing the elicitation of an established immune response. Irradiation with ultraviolet AI (340-400 nm) had no effect. Supporting a critical role for ultraviolet A in ultraviolet-induced immune suppression was the observation that applying a sunscreen that contained an ultraviolet B only filter had no protective effect, whereas, a sunscreen containing both ultraviolet A and ultraviolet B filters totally blocked ultraviolet-induced immune suppression. These data suggest that sunlight may depress the protective effect of prior vaccination. In addition, the observation that ultraviolet A is immunosuppressive indicates the need for ultraviolet A protection when designing sun protection strategies.