title: IL-22 capacitates dermal fibroblast responses to TNF in scleroderma.
abstract: Interleukin (IL) 22 mRNA in systemic sclerosis (SSc) skin and Th22 cells in SSc peripheral blood are increased, but the role of IL-22 in fibrosis development remains poorly understood.
  
  
  
  Biopsies were obtained from the involved skin of 15 SSc, 4 morphea and 8 healthy donors (HD). The presence of IL-22+ cells in the skin was determined by immunostaining. The in vitro response of HD and SSc fibroblasts to IL-22, IL-22 in conjunction with tumour necrosis factor (TNF) or keratinocyte conditioned medium was assessed by ELISA, radioimmunoassay (RIA), real-time PCR and western blot. The in vivo response in mice was assessed by histomorphometry.
  
  
  
  IL-22+ cells were over-represented in the dermis and epidermis of morphea and in the epidermis of SSc compared with HD. The majority of dermal IL-22+ cells were T cells. Dermal fibroblasts expressed both IL-22 receptor subunits IL-10RB and IL-22RA, expression of which was enhanced by TNF and reduced by transforming growth factor (TGF)-β. IL-22 induced rapid phosphorylation of p38 and ERK1/2 in fibroblasts, but failed to induce the synthesis of chemokines and extracellular matrix components. However, IL-22 enhanced the production of monocyte chemotactic protein 1, IL-8 and matrix metalloproteinase 1 induced by TNF. Fibroblast responses were maximal in the presence of conditioned medium from keratinocytes activated by IL-22 in conjunction with TNF. Dermal thickness was maximal in mice injected simultaneously with IL-22 and TNF.
  
  
  
  IL-22 capacitates fibroblast responses to TNF and promotes a proinflammatory fibroblast phenotype by favouring TNF-induced keratinocyte activation. These results define a novel role for keratinocyte-fibroblast interactions in the context of skin fibrosis.
authors.affiliation: Department of Immunology and Allergy, University Hospital and School of Medicine, Geneva, Switzerland Department of Dermatology, University Hospital and School of Medicine, Geneva, Switzerland Department of Pathology and Immunology, School of Medicine, Geneva, Switzerland.
authors.forename: Nicolò Costantino
authors.initials: NC
authors.lastname: Brembilla
authors.affiliation: Department of Immunology and Allergy, University Hospital and School of Medicine, Geneva, Switzerland Department of Pathology and Immunology, School of Medicine, Geneva, Switzerland.
authors.forename: Aleksandra Maria
authors.initials: AM
authors.lastname: Dufour
authors.affiliation: Department of Immunology and Allergy, University Hospital and School of Medicine, Geneva, Switzerland Department of Pathology and Immunology, School of Medicine, Geneva, Switzerland.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Alvarez
authors.affiliation: Department of Pathology and Immunology, School of Medicine, Geneva, Switzerland.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Hugues
authors.affiliation: Department of Immunology and Allergy, University Hospital and School of Medicine, Geneva, Switzerland.
authors.forename: Elisa
authors.initials: E
authors.lastname: Montanari
authors.affiliation: Department of Immunology and Allergy, University Hospital and School of Medicine, Geneva, Switzerland.
authors.forename: Marie-Elise
authors.initials: ME
authors.lastname: Truchetet
authors.affiliation: Department of Immunology and Allergy, University Hospital and School of Medicine, Geneva, Switzerland Experimental Laboratory of Immunological and Rheumatologic Researches, IRCSS Istituto Auxologico Italiano, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Lonati
authors.affiliation: Department of Dermatology, University Hospital and School of Medicine, Geneva, Switzerland.
authors.forename: Lionel
authors.initials: L
authors.lastname: Fontao
authors.affiliation: Department of Internal Medicine, Institute of Clinica Medica, Ancona, Italy.
authors.forename: Armando
authors.initials: A
authors.lastname: Gabrielli
authors.affiliation: Department of Rheumatology, Clinical and Experimental Medicine, Second University of Naples, Naples, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Vettori
authors.affiliation: Department of Rheumatology, Clinical and Experimental Medicine, Second University of Naples, Naples, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Valentini
authors.affiliation: Department of Dermatology, University Hospital and School of Medicine, Geneva, Switzerland Department of Pathology and Immunology, School of Medicine, Geneva, Switzerland.
authors.forename: Wolf-Henning
authors.initials: WH
authors.lastname: Boehncke
authors.affiliation: Experimental Laboratory of Immunological and Rheumatologic Researches, IRCSS Istituto Auxologico Italiano, Milan, Italy Division of Rheumatology, Istituto G Pini, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Meroni
authors.affiliation: Department of Immunology and Allergy, University Hospital and School of Medicine, Geneva, Switzerland Department of Pathology and Immunology, School of Medicine, Geneva, Switzerland.
authors.forename: Carlo
authors.initials: C
authors.lastname: Chizzolini
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D004817:Epidermis / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis; D006801:Humans; D007378:Interleukins / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D012594:Scleroderma, Localized / Q000378:metabolism / Q000473:pathology; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000473:pathology; D012867:Skin / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D055815:Young Adult; D000097043:Interleukin-22
chemical_list: D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D000097043:Interleukin-22
keywords: Autoimmune Diseases; Cytokines; Fibroblasts; Inflammation; Systemic Sclerosis