title: Protective role of systemic furin in immune response-induced arthritis.
abstract: OBJECTIVE
  Rheumatoid arthritis (RA) is an autoimmune joint disease associated with chronic inflammation of the synovium that causes profound damage of joints. Inflammation results in part from the influx of immune cells secreting inflammatory cytokines and the reduction in the number of Treg cells. We undertook this study to assess the effect of furin, a proteinase implicated in the proteolytic activity of various precursor proteins and involved in the regulation of both proteinase maturation and immune cells, in an experimental model of RA.
  
  
  METHODS
  The effect of furin and its inhibitor α1-PDX was tested in mice with collagen-induced arthritis (CIA). Joints were processed for histology and protein expression. Levels of cytokines were measured in joint tissue, and Treg cell numbers were measured in spleens.
  
  
  RESULTS
  Furin expression and activity were high in the synovial pannus in RA patients and mice with CIA. Systemic administration of furin prevented increases in the arthritis score, joint destruction, and bone loss, in contrast to systemic administration of the furin inhibitor α1-PDX, which enhanced these parameters. By preventing the development of synovial pannus, furin reduced the expression of metalloproteinases in the joints. In contrast, α1-PDX enhanced synovial proliferation and the expression and activity of matrix metalloproteinases. Furthermore, furin reversed the local Th1/Th2 balance and restored the number of Treg cells in the spleen, indicating mediation by immune cells.
  
  
  CONCLUSIONS
  These findings show the protective role of exogenous furin against RA, mediated by an immune response. The data suggest the potential therapeutic use of furin or its derivatives in autoimmune diseases including RA.
authors.affiliation: INSERM UMR-S 606, Université Paris-Diderot, and Hôpital Lariboisière, Paris, France.
authors.forename: Hilène
authors.initials: H
authors.lastname: Lin
authors.forename: Marie-Dominique
authors.initials: MD
authors.lastname: Ah Kioon
authors.forename: Claude
authors.initials: C
authors.lastname: Lalou
authors.forename: Jerome
authors.initials: J
authors.lastname: Larghero
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Launay
authors.forename: Abdel-Majid
authors.initials: AM
authors.lastname: Khatib
authors.forename: Martine
authors.initials: M
authors.lastname: Cohen-Solal
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D045683:Furin / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007596:Joints / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D012213:Rheumatic Fever / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000515:alpha 1-Antitrypsin / Q000494:pharmacology
chemical_list: D016207:Cytokines; D000515:alpha 1-Antitrypsin; C113421:alpha 1-antitrypsin Portland; D045683:Furin