title: Contact with stimulated T cells up-regulates expression of peptidylarginine deiminase 2 and 4 by human monocytes.
abstract: OBJECTIVE
  The antigenic targets of the rheumatoid arthritis (RA)-associated autoantibodies to "citrullinated" proteins are generated following citrullination by a peptidylarginine deiminase (PAD). Of the five PAD isotypes, two - PAD2 and PAD4 - are expressed in RA synovial tissue. Within this tissue, the activation of macrophages and fibroblasts mediated by T-cell contact or driven by cytokines plays a prominent part in the pathogenesis. We wanted to determine whether cytokine stimulation and contact with T cells could play a role in PAD expression by peripheral blood monocytes and fibroblastic synoviocytes.
  
  
  METHODS
  Human monocytes and T lymphocytes were derived from the blood of healthy donors. HUT-78 cells and T lymphocytes were stimulated with PHA and PMA. Human synovial fibroblasts were isolated after surgical synoviectomy. The expression of PAD was determined by real-time PCR and immunoblot.
  
  
  RESULTS
  In monocytes, the PADI2 and PADI4 mRNAs were transiently up-regulated by contact with stimulated HUT-78 and/or T lymphocytes. Positive modulation of the PAD2 and PAD4 proteins were also observed upon contact with stimulated HUT-78 T cells. Stimulation by IL-1β or IFN-β did not modify the PADI2 and PADI4 mRNAs, but enhanced PAD4 protein expression. No isotype of PAD was detected at the mRNA or protein level in resting or stimulated synovial fibroblasts.
  
  
  CONCLUSIONS
  Contact between stimulated T cells and monocyte-macrophages or cytokine-activated monocyte-macrophages constitutes a highly likely source of PAD2 and PAD4, which are observed in inflamed synovial tissues. In contrast, it is most unlikely that fibroblastic synoviocytes contribute to PAD expression in rheumatoid synovial membranes.
authors.affiliation: Clinical Immunology Unit, Division of Immunology and Allergy, Department of Internal Medicine, University Hospital and Faculty of Medicine, Geneva, Switzerland. sylvie.ferrari@hcuge.ch
authors.forename: Sylvie
authors.initials: S
authors.lastname: Ferrari-Lacraz
authors.forename: Mireille
authors.initials: M
authors.lastname: Sebbag
authors.forename: Rachel
authors.initials: R
authors.lastname: Chicheportiche
authors.forename: Céline
authors.initials: C
authors.lastname: Foulquier
authors.forename: Guy
authors.initials: G
authors.lastname: Serre
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dayer
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001323:Autoantibodies / Q000378:metabolism; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000096:biosynthesis* / Q000235:genetics; D016899:Interferon-beta / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology; D008213:Lymphocyte Activation; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D000080064:Protein-Arginine Deiminase Type 2; D000076342:Protein-Arginine Deiminases; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D001323:Autoantibodies; D053583:Interleukin-1beta; D012333:RNA, Messenger; D016899:Interferon-beta; D006867:Hydrolases; C000620352:PADI2 protein, human; D000080064:Protein-Arginine Deiminase Type 2; D000076342:Protein-Arginine Deiminases