title: Gingival fibroblasts grown from cyclosporin-treated patients show a reduced production of matrix metalloproteinase-1 (MMP-1) compared with normal gingival fibroblasts, and cyclosporin down-regulates the production of MMP-1 stimulated by pro-inflammatory cytokines.
abstract: OBJECTIVE
  Cyclosporin-induced gingival overgrowth arises from an alteration in collagen homeostasis and is enhanced by inflammatory changes in the gingival tissues. The aim of this study was to investigate the interaction among interleukin-1, oncostatin M, cyclosporin and nifedipine in promoting the up-regulation of matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinase by gingival fibroblasts.
  
  
  METHODS
  Fibroblast cultures (n = 5) were obtained from healthy controls and from patients with cyclosporin-induced gingival overgrowth, and cells were harvested between the fourth and ninth passages. Cells were stimulated with interleukin-1 and oncostatin M, alone or in combination, and with different concentrations of cyclosporin (0-2000 ng/mL) and nifedipine (0-200 ng/mL). MMP-1 and tissue inhibitor of metalloproteinase-1 production was determined using an enzyme-linked immunosorbent assay technique. A CyQuant cell proliferation assay was used to determine the DNA concentration in the sample.
  
  
  RESULTS
  Fibroblasts obtained from patients with cyclosporin-induced gingival overgrowth produced significantly lower levels of MMP-1 than control fibroblasts (p < 0.001); tissue inhibitor of metalloproteinase-1 levels were significantly lower (p < 0.05), and the ratio of MMP-1 to tissue inhibitor of metalloproteinase-1 was reduced, in the conditioned medium of patients with cyclosporin-induced gingival overgrowth compared with controls. Interleukin-1 and oncostatin M produced a significant increase in the up-regulation of MMP-1, which was reversed when cyclosporin and nifedipine were added to the cell cultures (p < 0.05).
  
  
  CONCLUSIONS
  Pro-inflammatory cytokines significantly up-regulate MMP-1 in cultured gingival fibroblasts. Up-regulation is attenuated by both cyclosporin and nifedipine. The interaction may account for the synergism between inflammation and cyclosporin-induced gingival overgrowth.
authors.affiliation: School of Dental Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne, UK.
authors.forename: T Z
authors.initials: TZ
authors.lastname: Sukkar
authors.forename: J M
authors.initials: JM
authors.lastname: Thomason
authors.forename: T E
authors.initials: TE
authors.lastname: Cawston
authors.forename: R
authors.initials: R
authors.lastname: Lakey
authors.forename: D
authors.initials: D
authors.lastname: Jones
authors.forename: J
authors.initials: J
authors.lastname: Catterall
authors.forename: R A
authors.initials: RA
authors.lastname: Seymour
mesh_terms: D002121:Calcium Channel Blockers / Q000494:pharmacology; D016022:Case-Control Studies; D002478:Cells, Cultured; D016572:Cyclosporine / Q000009:adverse effects / Q000494:pharmacology; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D005881:Gingiva / Q000166:cytology / Q000378:metabolism*; D019214:Gingival Overgrowth / Q000139:chemically induced / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects; D007375:Interleukin-1 / Q000502:physiology; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis*; D009543:Nifedipine / Q000494:pharmacology; D053683:Oncostatin M / Q000502:physiology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis*
chemical_list: D002121:Calcium Channel Blockers; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D019715:Tissue Inhibitor of Metalloproteinase-1; D053683:Oncostatin M; D016572:Cyclosporine; D020781:Matrix Metalloproteinase 1; D009543:Nifedipine