title: Interleukin-34 produced by human fibroblast-like synovial cells in rheumatoid arthritis supports osteoclastogenesis.
abstract: BACKGROUND
  Interleukin-34 (IL-34) is a recently defined cytokine, showing a functional overlap with macrophage colony stimulating factor (M-CSF). This study was undertaken to address the expression of IL-34 in rheumatoid arthritis (RA) patients and to investigate its regulation and pathogenic role in RA.
  
  
  METHODS
  IL-34 levels were determined in the RA synovium, synovial fluid (SF) and fibroblast-like synovial cells (FLS) by immunohistochemistry, real-time PCR, enzyme-linked immunosorbent assay and immunoblotting. RA activity was assessed using Disease Activity Score 28 (DAS28) activity in the plasma collected at baseline and one year after treatment. Conditioned media (CM) were prepared from RA FLS culture with tumor necrosis factor alpha (TNFα) for 24 hours and used for functional assay.
  
  
  RESULTS
  IL-34 was expressed in the synovium, SF, and FLS from RA patients. The production of IL-34 in FLS was up-regulated by TNFα in RA samples compared with osteoarthritis (OA) patients. Importantly, the preferential induction of IL-34 rather than M-CSF by TNFα in RAFLS was mediated by the transcription factor nuclear factor kappa B (NF-κB) and activation of c-Jun N-terminal kinase (JNK). IL-34 elevation in plasma from RA patients was decreased after the administration of disease-modifying anti-rheumatic drugs (DMARDs) in accordance with a decrease in DAS28. CM from RAFLS cultured with TNFα promoted chemotactic migration of human peripheral blood mononuclear cells (PBMCs) and subsequent osteoclast (OC) formation, effects that were attenuated by an anti-IL-34 antibody.
  
  
  CONCLUSIONS
  These data provide novel information about the production of IL-34 in RA FLS and indicate that IL-34 is an additional osteoclastogenic factor regulated by TNFα in RA, suggesting a discrete role of IL-34 in inflammatory RA diseases.
authors.affiliation: Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul 138-736, Korea.
authors.forename: Seung-Jun
authors.initials: SJ
authors.lastname: Hwang
authors.forename: Bongkun
authors.initials: B
authors.lastname: Choi
authors.forename: Soon-Suk
authors.initials: SS
authors.lastname: Kang
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Chang
authors.forename: Yong-Gil
authors.initials: YG
authors.lastname: Kim
authors.forename: Yeon-Ho
authors.initials: YH
authors.lastname: Chung
authors.forename: Dong Hyun
authors.initials: DH
authors.lastname: Sohn
authors.forename: Min Wook
authors.initials: MW
authors.lastname: So
authors.forename: Chang-Keun
authors.initials: CK
authors.lastname: Lee
authors.forename: William H
authors.initials: WH
authors.lastname: Robinson
authors.forename: Eun-Ju
authors.initials: EJ
authors.lastname: Chang
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013582:Synovial Fluid / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D017077:Culture Media, Conditioned; D016328:NF-kappa B; C488100:TXLNA protein, human; D014409:Tumor Necrosis Factor-alpha; D033921:Vesicular Transport Proteins; D048031:JNK Mitogen-Activated Protein Kinases