title: Control of fibroblast-like synoviocyte proliferation by macrophage migration inhibitory factor.
abstract: OBJECTIVE
  The hyperplasia of fibroblast-like synoviocytes (FLS) is considered essential to the evolution of joint destruction in rheumatoid arthritis (RA), but the mechanisms underlying FLS proliferation remain poorly understood. Macrophage migration inhibitory factor (MIF) is a cytokine that has recently been shown to exert proinflammatory effects on RA FLS. This study sought to identify the mechanisms of activation of FLS by MIF, and to assess the effects of MIF on synovial cell proliferation.
  
  
  METHODS
  Human RA FLS were treated with recombinant MIF, interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF alpha), and/or anti-MIF monoclonal antibodies (mAb). Proliferation was measured with tritiated thymidine incorporation. Nuclear factor kappa B (NF-kappa B) and mitogen-activated protein (MAP) kinase activation were measured with immunohistochemistry and Western blotting, respectively.
  
  
  RESULTS
  FLS proliferation was significantly increased by MIF. IL-1 beta and TNFalpha also induced proliferation, but these effects were prevented by neutralization with anti-MIF mAb. Activation of NF-kappa B was induced by IL-1 beta, but not by MIF. Anti-MIF mAb had no effect on IL-1 beta-induced NF-kappa B nuclear translocation. By contrast, MIF induced phosphorylation of extracellular signal-regulated kinase (ERK) MAP kinase. ERK antagonism, but not NF-kappa B antagonism, prevented the effect of MIF on FLS proliferation.
  
  
  CONCLUSIONS
  These data suggest that MIF may regulate RA synovial hyperplasia by acting directly and via involvement in the effects of IL-1 beta and TNFalpha. In addition, the effects of MIF on FLS activation are independent of NF-kappa B, and dependent on ERK MAP kinase. These data suggest an important therapeutic potential for MIF antagonism in RA.
authors.affiliation: Monash University Medical Centre, Clayton, Melbourne, Australia.
authors.forename: Derek
authors.initials: D
authors.lastname: Lacey
authors.forename: Annaleise
authors.initials: A
authors.lastname: Sampey
authors.forename: Robert
authors.initials: R
authors.lastname: Mitchell
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Lanie
authors.initials: L
authors.lastname: Santos
authors.forename: Michelle
authors.initials: M
authors.lastname: Leech
authors.forename: Eric
authors.initials: E
authors.lastname: Morand
mesh_terms: D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D006965:Hyperplasia; D007375:Interleukin-1 / Q000494:pharmacology; D008263:Macrophage Migration-Inhibitory Factors / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013583:Synovial Membrane / Q000201:enzymology / Q000473:pathology*
chemical_list: D007375:Interleukin-1; D008263:Macrophage Migration-Inhibitory Factors; D016328:NF-kappa B; D011994:Recombinant Proteins; D020928:Mitogen-Activated Protein Kinases