title: IL-1-induced receptor activator of NF-kappa B ligand in human periodontal ligament cells involves ERK-dependent PGE2 production.
abstract: Periodontitis, an inflammatory disorder of the supporting tissue of teeth, is one of the most common infectious diseases in humans. Periodontal pathogens promote inflammatory cytokines such as interleukin-1 (IL-1) and prostaglandin E2 (PGE2), resulting in alveolar bone destruction. In the present study, we examined the cellular and molecular mechanisms of IL-1-induced osteoclastogenesis using a coculture system of human periodontal ligament (PDL) cells and mouse spleen cells. IL-1alpha induced tartrate-resistant acid phosphatase positive (TRAP+) cell formation in a dose-dependent manner. IL-1alpha up-regulated receptor activator of NF-kappaB ligand (RANKL) and down-regulated osteoprotegerin (OPG) mRNA expression in PDL cells. The addition of cell-permeable PKI, an inhibitor of the cAMP/PKA signaling pathway, to the cocultures 8 h after the IL-1alpha stimulation inhibited IL-1alpha-induced TRAP+ cell formation. IL-1alpha-induced TRAP+ cell formation was completely blocked by either NS398, a selective inhibitor of cyclooxygenase (COX)-2, or PD98059, a specific inhibitor of extracellular signal-regulated kinase (ERK). Pretreatment with NS398 and PD98059 also inhibited both the up-regulation of RANKL and the down-regulation of OPG expression by IL-1alpha in PDL cells. IL-1alpha activated ERK phosphorylation and PD98059 greatly inhibited both COX-2 mRNA expression and PGE(2) production induced by IL-1alpha in PDL cells. In contrast, NEMO binding domain (NBD) peptide, a specific inhibitor of NF-kappaB signaling, did not affect COX2, RANKL, or OPG mRNA expression induced by IL-1alpha. These results suggest that IL-1alpha stimulates osteoclast formation by increasing the expression level of RANKL versus OPG via ERK-dependent PGE2 production in PDL cells.
authors.affiliation: Department of Physiological Science and Molecular Biology, Fukuoka Dental College, Fukuoka, 814-0193, Japan.
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Fukushima
authors.forename: Eijiro
authors.initials: E
authors.lastname: Jimi
authors.forename: Fujio
authors.initials: F
authors.lastname: Okamoto
authors.forename: Wataru
authors.initials: W
authors.lastname: Motokawa
authors.forename: Koji
authors.initials: K
authors.lastname: Okabe
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D015232:Dinoprostone / Q000096:biosynthesis* / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000096:biosynthesis* / Q000235:genetics; D053244:Osteoprotegerin; D010513:Periodontal Ligament / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D010519:Periodontium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D005419:Flavonoids; D006023:Glycoproteins; D007375:Interleukin-1; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D015232:Dinoprostone; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one