title: Porphyromonas gingivalis enhances FasL expression via up-regulation of NFkappaB-mediated gene transcription and induces apoptotic cell death in human gingival epithelial cells.
abstract: The interaction between epithelial cells and micro-organisms is often a crucial initiating event in infectious diseases. Infection with Porphyromonas gingivalis, a Gram-negative anaerobe, is strongly associated with severe periodontal disease. This bacterium possesses an array of virulence factors, some of which can induce apoptosis. The tumour necrosis factor (TNF) receptor family is involved in the regulation of cellular homeostasis, cell surface molecules involved in phagocytosis, Fas ligand (L) expression and activation of the caspase cascade resulting in DNA fragmentation and cell blebbing. The current study examined the role of nuclear factor-kappaB (NFkappaB) in FasL-mediated apoptotic cell death in primary human gingival epithelial cells (HGEC) induced by heat-killed P. gingivalis, probably through TLR signalling pathways. A marked up-regulation of TLR2 and Fas-FasL was detected in HGEC stimulated with P. gingivalis. Activation of NFkappaB by P. gingivalis in HGEC was demonstrated by an NFkappaB promoter luciferase assay as well as by phosphorylation of p65 as detected by Western blotting. Activation of cleaved caspase-3 and caspase-8 resulted in apoptotic cell death of HGEC. The survival proteins c-IAP-1/c-IAP-2 were decreased in HGEC exposed to P. gingivalis. HGEC apoptosis induced by P. gingivalis was inhibited by an anti-human FasL monoclonal antibody. Blockade of NFkappaB by helenalin resulted in down-regulation of FasL whereas a caspase-8 inhibitor did not decrease FasL. Taken together, these studies show that P. gingivalis can induce epithelial cell apoptosis through Fas-FasL up-regulation and activation of caspase-3 and caspase-8.
authors.affiliation: Oral Health and Systemic Diseases, School of Dentistry, University of Louisville, 501 South Preston Street, Louisville, KY 40202, USA.
authors.forename: Suzana
authors.initials: S
authors.lastname: Brozovic
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology/Hepatology, School of Medicine, University of Louisville Medical Center, Louisville, KY 40292, USA.
authors.forename: Rashmita
authors.initials: R
authors.lastname: Sahoo
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology/Hepatology, School of Medicine, University of Louisville Medical Center, Louisville, KY 40292, USA.
authors.forename: Shirish
authors.initials: S
authors.lastname: Barve
authors.affiliation: Oral Health and Systemic Diseases, School of Dentistry, University of Louisville, 501 South Preston Street, Louisville, KY 40202, USA.
authors.forename: Hideki
authors.initials: H
authors.lastname: Shiba
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology/Hepatology, School of Medicine, University of Louisville Medical Center, Louisville, KY 40292, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Uriarte
authors.affiliation: Laboratory of Mucosal Immunology at Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
authors.affiliation: Oral Health and Systemic Diseases, School of Dentistry, University of Louisville, 501 South Preston Street, Louisville, KY 40202, USA.
authors.forename: Denis F
authors.initials: DF
authors.lastname: Kinane
mesh_terms: D017209:Apoptosis; D004847:Epithelial Cells / Q000382:microbiology; D053222:Fas Ligand Protein; D005881:Gingiva / Q000166:cytology / Q000382:microbiology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D016966:Porphyromonas gingivalis / Q000472:pathogenicity*; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D014158:Transcription, Genetic; D048069:Tumor Necrosis Factors / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D048069:Tumor Necrosis Factors