A Common Pathway for Ultraviolet Radiation–Induced Immunosuppression

UV light induces immunosuppression, and the process appears to be linked to mechanisms of DNA repair.

Ultraviolet (UV) radiation causes sunburn, skin cancer, and photoaging; it also induces a subtle form of immunosuppression that is implicated in the development of nonmelanoma skin cancers and is thought to explain phototherapy's benefits in inflammatory skin diseases. The precise mechanism underlying UV-related immunosuppression has occasioned considerable interest. UV-induced DNA damage, activation of platelet-activation–factor (PAF) signal transduction pathways, photoconversion of trans-urocanic acid (a molecule found in the stratum corneum) to cis-urocanic acid, and the generation of reactive oxygen intermediates have all been implicated. How do these diverse factors serve as intermediaries for the suppressive effects of UV radiation? Investigators addressed this issue, finding some common links in the inhibition of DNA repair processes.

Antagonists of the PAF and serotonin receptors (which bind cis-urocanic acid) blocked UV-induced immunosuppression and decreased the number of cyclobutane pyrimidine dimers and 6-4 photoproducts (UV-induced lesions) in UVB-irradiated mouse skin. Moreover, exposing UV-irradiated keratinocytes to inhibitors of the PAF and serotonin receptors increased nucleotide excision repair. Although the antagonists accelerated the removal of cyclobutane pyrimidine dimers and 6-4 photoproducts in UV-irradiated normal mice, they had no effect in mice lacking DNA repair enzymes. PAF and cis-urocanic acid also augmented generation of reactive oxygen intermediates. Blocking either of these pathways decreased oxidative DNA damage.

Comment

These results suggest that the effects of UV radiation on cis-urocanic acid, PAF, and reactive oxygen intermediates proceed through a common pathway to initiate UV-induced immunosuppression. Specifically, cis-urocanic acid is generated in the skin, and PAF pathways are triggered after UV exposure. Both processes stimulate the production of reactive oxygen intermediates, which further augment genetic damage by producing oxidative lesions in DNA. The DNA damage (cyclobutane pyrimidine dimers, 6-4 photoproducts, and oxidative changes) then leads to immunosuppression. Understanding the mechanisms of UV immunosuppression can help us develop new approaches to skin cancer prevention and safer, more effective phototherapeutic techniques.

Reviewing Author

Craig A. Elmets, MD

Disclosures

Consultant / Advisory board Astellas Pharmaceuticals

EquityVaxin

Grant / Research support NIH; NIH/NCI; Veteran’s Administration; Ferndale Laboratories; Kyowa Hakko Kirin Pharma, Inc.

Editorial boards Cancer Prevention Research; Photodermatology, Photoimmunology, & Photomedicine; UpToDate; eMedicine; Journal of Dermatological Sciences; JAMA Dermatology

Leadership positions in professional societies American Academy of Dermatology (Vice Chair, Committee on Science and Research); Photomedicine Society (Board of Directors)