title: IL-36γ sustains a proinflammatory self-amplifying loop with IL-17C in anti-TNF-induced psoriasiform skin lesions of patients with Crohn's disease.
abstract: BACKGROUND
  Anti-tumor necrosis factor (TNF) therapy-induced psoriasiform skin lesions are a recently described side effect in patients with inflammatory bowel disease. Interleukin (IL)-12/IL-23 neutralization is an effective therapy for these lesions. As Th17 cytokines, such as IL-17A, and IL-1 family members, such as IL-36, play a significant role in plaque psoriasis, we analyzed the involvement of IL-17C and IL-36γ in anti-TNF-induced skin lesions of patients with Crohn's disease.
  
  
  METHODS
  IL-36γ and IL-17C levels in biopsies of anti-TNF-induced psoriasiform skin lesions of patients with Crohn's disease were assessed by immunohistochemical analysis and correlated to additional immunohistochemical data. IL-36γ and IL-17C messenger RNA, protein, and induced gene expression in human primary keratinocytes were analyzed using quantitative real-time polymerase chain reaction, immunoblotting, and enzyme-linked immunosorbent assay.
  
  
  RESULTS
  IL-36γ and IL-17C are increased in anti-TNF-induced psoriasiform skin lesions of patients with Crohn's disease, compared with healthy controls. Epidermal IL-36γ and IL-17C levels strongly correlate with each other (r = 0.748, P = 0.003). In contrast to IL-12 and IL-23, IL-36γ increases the expression of proinflammatory signals and effector molecules of innate immunity in keratinocytes. However, IL-17C affects keratinocyte defensin gene expression only in combination with TNF-α. IL-36γ induces TNF-α expression in keratinocytes and sustains a self-amplifying proinflammatory loop with IL-17C by inducing its own expression and that of IL-17C.
  
  
  CONCLUSIONS
  Our study demonstrates a unique role of the previously unknown self-amplifying, proinflammatory IL-36γ/IL-17C loop in the pathogenesis of anti-TNF-induced psoriasiform skin lesions. These findings suggest a beneficial effect of IL-36γ/IL-17C inhibition during anti-TNF-induced psoriasiform lesions in patients with inflammatory bowel disease.
authors.affiliation: *Department of Medicine II, University-Hospital Munich-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany; †Clinic for Preventive Dentistry and Parodontology, Ludwig-Maximilians-University, Munich, Germany; and ‡Department of Dermatology and Allergy, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Friedrich
authors.forename: Cornelia
authors.initials: C
authors.lastname: Tillack
authors.forename: Andreas
authors.initials: A
authors.lastname: Wollenberg
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schauber
authors.forename: Stephan
authors.initials: S
authors.lastname: Brand
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects*; D002478:Cells, Cultured; D015331:Cohort Studies; D003424:Crohn Disease / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D018836:Inflammation Mediators / Q000378:metabolism*; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011565:Psoriasis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C508589:IL36G protein, human; D018836:Inflammation Mediators; D007375:Interleukin-1; D020381:Interleukin-17; D007378:Interleukins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha