title: 8-methoxypsoralen plus ultraviolet A therapy acts via inhibition of the IL-23/Th17 axis and induction of Foxp3+ regulatory T cells involving CTLA4 signaling in a psoriasis-like skin disorder.
abstract: To elucidate the molecular action of 8-methoxypsoralen plus UVA (PUVA), a standard dermatological therapy, we used K5.hTGF-beta1 transgenic mice exhibiting a skin phenotype and cytokine abnormalities with strong similarities to human psoriasis. We observed that impaired function of CD4+CD25+ regulatory T cells (Tregs) and increased cytokine levels of the IL-23/Th17 pathway were responsible for the psoriatic phenotype in this mouse model. Treatment of K5.hTGF-beta1 transgenic mice with PUVA suppressed the IL-23/Th17 pathway, Th1 milieu, as well as transcription factors STAT3 and orphan nuclear receptor RORgammat. PUVA induced the Th2 pathway and IL-10-producing CD4+CD25+Foxp3+Tregs with disease-suppressive activity that was abolished by anti-CTLA4 mAb treatment. These findings were paralleled by macroscopic and microscopic clearance of the diseased murine skin. Anti-IL-17 mAb treatment also diminished the psoriatic phenotype of the mice. This indicated that both induced Tregs involving CTLA4 signaling and inhibition of the IL-23/Th17 axis are central for the therapeutic action of PUVA.
authors.affiliation: Research Unit for Photodermatology, Department of Dermatology, Medical University of Graz, Graz, Austria.
authors.forename: Tej Pratap
authors.initials: TP
authors.lastname: Singh
authors.forename: Michael P
authors.initials: MP
authors.lastname: Schön
authors.forename: Katrin
authors.initials: K
authors.lastname: Wallbrecht
authors.forename: Kai
authors.initials: K
authors.lastname: Michaelis
authors.forename: Beate
authors.initials: B
authors.lastname: Rinner
authors.forename: Gerlinde
authors.initials: G
authors.lastname: Mayer
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schmidbauer
authors.forename: Heimo
authors.initials: H
authors.lastname: Strohmaier
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Wang
authors.forename: Peter
authors.initials: P
authors.lastname: Wolf
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000187:drug effects / Q000276:immunology / Q000528:radiation effects; D060908:CTLA-4 Antigen; D002469:Cell Separation; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D051858:Forkhead Transcription Factors / Q000187:drug effects / Q000276:immunology / Q000528:radiation effects; D006801:Humans; D007118:Immunoassay; D007150:Immunohistochemistry; D020381:Interleukin-17 / Q000528:radiation effects*; D053759:Interleukin-23 / Q000187:drug effects* / Q000528:radiation effects; D008730:Methoxsalen / Q000008:administration & dosage*; D051379:Mice; D008822:Mice, Transgenic; D017319:Photosensitizing Agents / Q000008:administration & dosage*; D010789:Phototherapy; D011565:Psoriasis / Q000276:immunology / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology / Q000528:radiation effects; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000528:radiation effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000528:radiation effects; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology; D014466:Ultraviolet Rays
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D053759:Interleukin-23; D017319:Photosensitizing Agents; D016212:Transforming Growth Factor beta; D008730:Methoxsalen