title: Macrophage-derived delta-like protein 1 enhances interleukin-6 and matrix metalloproteinase 3 production by fibroblast-like synoviocytes in mice with collagen-induced arthritis.
abstract: OBJECTIVE
  We previously reported that blockade of the Notch ligand delta-like protein 1 (DLL-1) suppressed osteoclastogenesis and ameliorated arthritis in a mouse model of rheumatoid arthritis (RA). However, the mechanisms by which joint inflammation were suppressed have not yet been revealed. This study was undertaken to determine whether DLL-1 regulates the production of RA-related proinflammatory cytokines.
  
  
  METHODS
  Joint cells from mice with collagen-induced arthritis (CIA) and mouse fibroblast-like synoviocytes (FLS) were cultured with or without stimuli in the presence of neutralizing antibodies against Notch ligands, and the production of proinflammatory cytokines was determined by enzyme-linked immunosorbent assay. The expression of Notch receptors and ligands on mouse joint cells was determined by flow cytometry.
  
  
  RESULTS
  The production of interleukin-6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF) by mouse joint cells with or without stimulation was suppressed by DLL-1 blockade. DLL-1 blockade also suppressed the levels of IL-6 and matrix metalloproteinase 3 (MMP-3) in the joint fluid in a mouse model of RA. However, the production of tumor necrosis factor α and IL-1β was not suppressed by DLL-1 blockade. The production of IL-6 and MMP-3 by mouse FLS was enhanced by DLL-1 stimulation as well as Notch-2 activation. Among joint cells, DLL-1 was not expressed on mouse FLS but was expressed on macrophages.
  
  
  CONCLUSIONS
  These results suggest that the interaction of DLL-1 on mouse joint macrophages with Notch-2 on mouse FLS enhances the production of IL-6 and MMP-3. Therefore, suppression of IL-6, GM-CSF, and MMP-3 production by DLL-1 blockade might be responsible for the amelioration of arthritis in a mouse model of RA.
authors.affiliation: Juntendo University School of Medicine, Tokyo, Japan, and Teikyo University School of Medicine, Tokyo, Japan.
authors.forename: Chiyoko
authors.initials: C
authors.lastname: Sekine
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nanki
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D007596:Joints / Q000378:metabolism; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D051379:Mice; D008811:Mice, Inbred DBA; D013582:Synovial Fluid / Q000378:metabolism; D013583:Synovial Membrane / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019278:Matrix Metalloproteinase 3