title: Glycogen synthase kinase-3 beta inhibitor suppresses Porphyromonas gingivalis lipopolysaccharide-induced CD40 expression by inhibiting nuclear factor-kappa B activation in mouse osteoblasts.
abstract: Bone-forming osteoblasts have been recently reported capable of expressing the critical co-stimulatory molecule CD40 upon exposure to bacterial infection, which supports the unappreciated role of osteoblasts in modulating bone inflammation. Recent studies highlight the anti-inflammatory potential of glycogen synthase kinase-3β (GSK-3β) inhibitors; however, their effect on osteoblasts remains largely unclear. In the present study, we showed that treatment with SB216763, a highly specific GSK-3β inhibitor, resulted in a dose-dependent decrease in the mRNA and protein expression of CD40, as well as production of pro-inflammatory cytokines IL-6, TNF-α and IL-1β, in the Porphyromonas gingivalis-lipopolysaccharide (LPS)-stimulated murine osteoblastic-like MC3T3-E1 cells. Furthermore, inhibition of GSK-3β remarkably represses the LPS-induced activation of the nuclear factor kappa B (NF-κB) signaling pathway by suppressing IκBα phosphorylation, NF-κBp65 nuclear translocation, and NF-κBp65 DNA binding activity. Closer investigation by immunoprecipitation assay revealed that β-catenin can physically interact with NF-κBp65. The negative regulation effect of GSK-3β inhibitor on CD40 expression is mediated through β-catenin, for siRNA of β-catenin attenuated the GSK-3β inhibitor-induced repression of NF-κB activation and, consequently, the expression of CD40 and production of pro-inflammatory cytokines in LPS-stimulated MC3T3-E1 cells. Thus our results elucidate the molecular mechanisms whereby GSK-3β inhibitor prevents the LPS-induced CD40 expression on osteoblasts and provide supportive evidence of the potential role of GSK-3β inhibitors in suppressing the immune function of osteoblasts in inflammatory bone diseases.
authors.affiliation: Sichuan University, State Key Laboratory of Oral Disease, West China College of Stomatology, 14 Renminnan Road, Chengdu 610041, Sichuan, China. llmld@126.com
authors.forename: Liu
authors.initials: L
authors.lastname: Die
authors.forename: Peng
authors.initials: P
authors.lastname: Yan
authors.forename: Zhai
authors.initials: Z
authors.lastname: Jun Jiang
authors.forename: Teng
authors.initials: T
authors.lastname: Min Hua
authors.forename: Wen
authors.initials: W
authors.lastname: Cai
authors.forename: Liang
authors.initials: L
authors.lastname: Xing
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D019013:CD40 Antigens / Q000235:genetics*; D016207:Cytokines / Q000096:biosynthesis; D015870:Gene Expression / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D016966:Porphyromonas gingivalis / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism
chemical_list: D019013:CD40 Antigens; C495267:CTNNB1 protein, mouse; D016207:Cytokines; D007166:Immunosuppressive Agents; D007211:Indoles; D008070:Lipopolysaccharides; D008301:Maleimides; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C417521:SB 216763; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3