title: Fusobacterium nucleatum increases collagenase 3 production and migration of epithelial cells.
abstract: Fusobacterium nucleatum is closely associated with human periodontal diseases and may also be a causative agent in other infections, such as pericarditis, septic arthritis, and abscesses of tonsils and liver. Initiation and outcome of infective diseases depend critically on the host cell signaling system altered by the microbe. Production of proteinases by infected cells is an important factor in pericellular tissue destruction and cell migration. We studied binding of F. nucleatum to human epithelial cells (HaCaT keratinocyte line) and subsequent cell signaling related to collagenase 3 expression, cell motility, and cell survival, using a scratch wound cell culture model. F. nucleatum increased levels of 12 protein kinases involved in cell migration, proliferation, and cell survival signaling, as assessed by the Kinetworks immunoblotting system. Epithelial cells of the artificial wound margins were clearly preferential targets of F. nucleatum. The bacterium colocalized with lysosomal structures and stimulated migration of these cells. Of the 13 anaerobic oral bacterial species, F. nucleatum and Fusobacterium necrophorum were among the best inducers of collagenase 3 mRNA levels, a powerful matrix metalloproteinase. Production of collagenase 3 was detected in fusobacterium-infected cells and cell culture medium by immunocytochemistry, immunoblotting, and zymography. The proteinase production involved activation of p38 mitogen-activated protein kinase in the infected cells. The study suggests that F. nucleatum may be involved in the pathogenesis of periodontal diseases (and other infections) by activating multiple cell signaling systems that lead to stimulation of collagenase 3 expression and increased migration and survival of the infected epithelial cells.
authors.affiliation: University of Helsinki, Institute of Dentistry, PL 41, FIN-00014 University of Helsinki, Finland. jukka.uitto@helsinki.fi
authors.forename: Veli-Jukka
authors.initials: VJ
authors.lastname: Uitto
authors.forename: Daniel
authors.initials: D
authors.lastname: Baillie
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wu
authors.forename: Renee
authors.initials: R
authors.lastname: Gendron
authors.forename: Daniel
authors.initials: D
authors.lastname: Grenier
authors.forename: Edward E
authors.initials: EE
authors.lastname: Putnins
authors.forename: Arja
authors.initials: A
authors.lastname: Kanervo
authors.forename: James D
authors.initials: JD
authors.lastname: Firth
mesh_terms: D002465:Cell Movement / Q000502:physiology*; D017364:Collagenases / Q000378:metabolism*; D005674:Fusobacterium Infections / Q000378:metabolism*; D016967:Fusobacterium nucleatum / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D053509:Matrix Metalloproteinase 13; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D048051:p38 Mitogen-Activated Protein Kinases; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020780:Matrix Metalloproteinase 9