Priming effect of fibronectin fragments on the macrophage inflammatory response: potential contribution to periodontitis.
Fibronectin, an extracellular matrix component, is a substrate for multiple host and bacterial proteinases found in inflamed periodontal sites. In the present study, we investigated the potential contribution of various fibronectin fragments to the inflammatory process of periodontitis. Our results showed that the smaller fragments of fibronectin (30 and 45 kDa) were the most potent inflammatory inducers as they dose-dependently increased the secretion of TNF-α, IL-1β, and IL-8 by human macrophages. The 120-kDa fragment did not induce the secretion of all the cytokines tested, while intact fibronectin only increased IL-8 secretion and to a lesser extent TNF-α secretion. Cytokine secretion was associated with increased amounts of phosphorylated ERK1/2, JNK2, and p38α MAPK in treated macrophages. The combination of fibronectin or fibronectin fragments with Porphyromonas gingivalis lipopolysaccharide had an additive effect, but no synergism appeared to occur. It was also demonstrated that gingival crevicular fluid samples recovered from patients with moderate to severe periodontitis contained more fibronectin fragments than samples obtained from healthy subjects. Finally, both Arg- and Lys-gingipains purified from P. gingivalis were found to modulate fibronectin fragmentation. In conclusion, we showed that specific fibronectin fragments that may be present in diseased periodontal sites may contribute to maintaining and amplifying the inflammatory state and that P. gingivalis gingipains may be involved in the production of these fragments.
Groupe de Recherche en Écologie Buccale, Faculté de Médecine Dentaire, Université Laval, 2420 Rue de la Terrasse, Quebec City, QC, Canada, G1V 0A6.
Karine
K
Feghali
Daniel
D
Grenier
D018829:Adhesins, Bacterial / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005353:Fibronectins / Q000276:immunology*; D000080867:Gingipain Cysteine Endopeptidases; D005883:Gingival Crevicular Fluid / Q000276:immunology; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D010518:Periodontitis / Q000276:immunology* / Q000382:microbiology; D010766:Phosphorylation; D016966:Porphyromonas gingivalis / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018829:Adhesins, Bacterial; D005353:Fibronectins; D000080867:Gingipain Cysteine Endopeptidases; D053583:Interleukin-1beta; D016209:Interleukin-8; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D003546:Cysteine Endopeptidases