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IL-22 capacitates dermal fibroblast responses to TNF in scleroderma
  1. Nicolò Costantino Brembilla1,2,3,
  2. Aleksandra Maria Dufour1,3,
  3. Montserrat Alvarez1,3,
  4. Stéphanie Hugues3,
  5. Elisa Montanari1,
  6. Marie-Elise Truchetet1,
  7. Paola Lonati1,4,
  8. Lionel Fontao2,
  9. Armando Gabrielli5,
  10. Serena Vettori6,
  11. Gabriele Valentini6,
  12. Wolf-Henning Boehncke2,3,
  13. Pierluigi Meroni4,7,
  14. Carlo Chizzolini1,3
  1. 1Department of Immunology and Allergy, University Hospital and School of Medicine, Geneva, Switzerland
  2. 2Department of Dermatology, University Hospital and School of Medicine, Geneva, Switzerland
  3. 3Department of Pathology and Immunology, School of Medicine, Geneva, Switzerland
  4. 4Experimental Laboratory of Immunological and Rheumatologic Researches, IRCSS Istituto Auxologico Italiano, Milan, Italy
  5. 5Department of Internal Medicine, Institute of Clinica Medica, Ancona, Italy
  6. 6Department of Rheumatology, Clinical and Experimental Medicine, Second University of Naples, Naples, Italy
  7. 7Division of Rheumatology, Istituto G Pini, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
  1. Correspondence to Dr Carlo Chizzolini, Department of Immunology and Allergy, University Hospital, Rue Gabrielle Perret-Gentil 4, 1211 Geneva 14, Switzerland; carlo.chizzolini{at}unige.ch

Abstract

Objectives 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.

Methods 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.

Results 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.

Conclusions 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.

  • Systemic Sclerosis
  • Fibroblasts
  • Cytokines
  • Inflammation
  • Autoimmune Diseases

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