title: Inhibition of UV-induced uric acid production using allopurinol prevents suppression of the contact hypersensitivity response.
abstract: Exposure to solar ultraviolet (UV) radiation suppresses adaptive immune responses. This contributes to skin carcinogenesis but may protect from some autoimmune diseases. However, the molecular changes occurring within UV-exposed skin that precipitate the downstream events leading to immune suppression are not fully understood. Using a combination of in vitro and in vivo mouse models, we have discovered that UV induces significant cutaneous production of immune suppressive uric acid. The ability of UV-induced uric acid to inhibit a contact hypersensitivity response was successfully blocked by the gout-treating drug Allopurinol. Up-regulation of NLRP3 mRNA by UV was also found to be dependent on UV-induced uric acid. This suggested that the target of UV-induced uric acid included proteins involved in the formation and activation of the NLRP3-inflammasome. However, in contrast to NLRP3, the adaptor protein ASC, which is required for formation of the NLRP3-inflammasome, was significantly down-regulated. Furthermore, this down-regulation was not dependent on UV-induced uric acid production because Allopurinol treatment failed to prevent the reduction in ASC. Hence, our results identify uric acid as an important molecule involved in sterile UV-induced inflammation and immune suppression. UV-induced uric acid may therefore offer a unique therapeutic target for preventing and treating skin cancer.
authors: Discipline of Infectious Diseases and Immunology, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors: Sarah
authors: S
authors: Leighton
authors: Lai-Fong
authors: LF
authors: Kok
authors: Gary M
authors: GM
authors: Halliday
authors: Scott N
authors: SN
authors: Byrne
mesh_terms: D000493:Allopurinol / Q000494:pharmacology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003877:Dermatitis, Contact / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006074:Gout Suppressants / Q000494:pharmacology; D007165:Immunosuppression Therapy; D066298:In Vitro Techniques; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012867:Skin / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D014466:Ultraviolet Rays / Q000009:adverse effects*; D015854:Up-Regulation / Q000187:drug effects; D014527:Uric Acid / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D006074:Gout Suppressants; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D014527:Uric Acid; D000493:Allopurinol