title: Cytokine pattern determines the progression of experimental periodontal disease induced by Actinobacillus actinomycetemcomitans through the modulation of MMPs, RANKL, and their physiological inhibitors.
abstract: OBJECTIVE
  Inflammatory and immune reactions raised in response to periodontopathogens are thought to trigger periodontal tissue destruction. We therefore investigated the expression of matrix metalloproteinases (MMPs) and the osteoclastogenic factor RANKL (receptor activator of nuclear factor-kappaB ligand), their respective inhibitors TIMPs (tissue inhibitors of metalloproteinases) and OPG (osteoprotegerin) and their possible correlation with the expression of inflammatory and regulatory cytokines in the course of experimental periodontal disease in mice.
  
  
  METHODS
  We characterized the time course of leukocyte migration and alveolar bone loss in C57BL/6 mice infected with Actinobacillus actinomycetemcomitans. Quantitative polymerase chain reaction (RealTime PCR) and ELISA were performed to determine the expression of MMPs, TIMPs, RANKL, OPG and cathepsin K, interleukin-1beta, tumor necrosis factor-alpha, interferon-gamma, interleukin-12, interleukin-4 and interleukin-10 in periodontal tissue samples harvested throughout the course of experimental disease.
  
  
  RESULTS
  Oral inoculation of A. actinomycetemcomitans results in an intense and widespread migration of leukocytes to the gingival tissues, besides marked alveolar bone resorption. Our data also demonstrate two distinct patterns of MMP/TIMP and RANKL/OPG expression in the course of experimental periodontal disease. The expression of MMPs (MMP-1, 2 and 9) and RANKL was correlated with the expression of interleukin-1beta, tumor necrosis factor-alpha and interferon-gamma, in a time period characterized by the intense increase of inflammatory reaction and alveolar bone loss. On the other hand, interleukin-4 and interleukin-10 were associated with higher expression of TIMPs (TIMP 1, 2 and 3) and OPG, with a lower expression of MMPs and RANKL, and with reduced rates of increase of cellular infiltration in periodontal tissues and alveolar bone loss.
  
  
  CONCLUSIONS
  It is possible that the pattern of cytokines produced in periodontal tissues determines the progression and the severity of experimental periodontal disease, controlling the breakdown of soft and bone tissues through the balance between MMPs/TIMP and RANKL/OPG expression in gingival tissues.
authors.affiliation: Department of Biochemistry and Immunology, School of Medicine-USP, Ribeirao Preto, SP, Brazil. gustavo@rpm.fmrp.usp.br
authors.forename: G P
authors.initials: GP
authors.lastname: Garlet
authors.forename: C R
authors.initials: CR
authors.lastname: Cardoso
authors.forename: T A
authors.initials: TA
authors.lastname: Silva
authors.forename: B R
authors.initials: BR
authors.lastname: Ferreira
authors.forename: M J
authors.initials: MJ
authors.lastname: Avila-Campos
authors.forename: F Q
authors.initials: FQ
authors.lastname: Cunha
authors.forename: J S
authors.initials: JS
authors.lastname: Silva
mesh_terms: D000189:Actinobacillus Infections / Q000276:immunology*; D016976:Aggregatibacter actinomycetemcomitans / Q000276:immunology*; D016301:Alveolar Bone Loss / Q000276:immunology / Q000382:microbiology; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000276:immunology*; D056657:Cathepsin K; D002403:Cathepsins / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D003546:Cysteine Endopeptidases / Q000276:immunology; D016207:Cytokines / Q000276:immunology*; D018450:Disease Progression; D006023:Glycoproteins / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D007378:Interleukins / Q000276:immunology; D007962:Leukocytes / Q000276:immunology; D008024:Ligands; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053244:Osteoprotegerin; D010510:Periodontal Diseases / Q000276:immunology / Q000382:microbiology*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000276:immunology*; D019714:Tissue Inhibitor of Metalloproteinases / Q000276:immunology; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000037:antagonists & inhibitors / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D006023:Glycoproteins; D007378:Interleukins; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D019714:Tissue Inhibitor of Metalloproteinases; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D056657:Cathepsin K; C534132:Ctsk protein, mouse; D020782:Matrix Metalloproteinases