title: PLAP-1/Asporin Regulates TLR2- and TLR4-induced Inflammatory Responses.
abstract: Periodontal ligament-associated protein 1 (PLAP-1)/asporin is an extracellular matrix protein preferentially expressed in periodontal ligaments. PLAP-1/asporin inhibits the cytodifferentiation and mineralization of periodontal ligament cells and has important roles in the maintenance of periodontal tissue homeostasis. However, the involvement of PLAP-1/asporin in inflammatory responses during periodontitis is poorly understood. This study hypothesized that PLAP-1/asporin might affect the pathogenesis of periodontitis by regulating periodontopathic bacteria-induced inflammatory responses. Proinflammatory cytokine expression induced by Toll-like receptor 2 (TLR2) and TLR4 was significantly downregulated when PLAP-1/asporin was overexpressed in periodontal ligament cells. Similarly, recombinant PLAP-1/asporin inhibited TLR2- and TLR4-induced proinflammatory cytokine expression in macrophages. We also confirmed that NF-κB activity induced by TLR2 and TLR4 signaling was suppressed by the addition of recombinant PLAP-1/asporin. Furthermore, IκB kinase α degradation induced by TLR4 was reduced by PLAP-1/asporin. Immunoprecipitation assays demonstrated the binding abilities of PLAP-1/asporin to both TLR2 and TLR4. Taken together, PLAP-1/asporin negatively regulates TLR2- and TLR4-induced inflammatory responses through direct molecular interactions. These findings indicate that PLAP-1/asporin has a defensive role in periodontitis lesions by suppressing pathophysiologic TLR signaling and that the modulating effects of PLAP-1/asporin might be useful for periodontal treatments.
authors.affiliation: Department of Periodontology, Osaka University Graduate School, Suita, Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Yamaba
authors.affiliation: Department of Periodontology, Osaka University Graduate School, Suita, Osaka, Japan satoru@dent.osaka-u.ac.jp.
authors.forename: S
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Department of Periodontology, Osaka University Graduate School, Suita, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kajikawa
authors.affiliation: Department of Periodontology, Osaka University Graduate School, Suita, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Awata
authors.affiliation: Department of Periodontology, Osaka University Graduate School, Suita, Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Sakashita
authors.affiliation: Department of Periodontology, Osaka University Graduate School, Suita, Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Tsushima
authors.affiliation: Department of Periodontology, Osaka University Graduate School, Suita, Osaka, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Fujihara
authors.affiliation: Department of Periodontology, Osaka University Graduate School, Suita, Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Yanagita
authors.affiliation: Department of Periodontology, Osaka University Graduate School, Suita, Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Murakami
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D016326:Extracellular Matrix Proteins / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D047468:Immunoprecipitation; D007249:Inflammation / Q000503:physiopathology*; D051379:Mice; D016328:NF-kappa B / Q000502:physiology; D010518:Periodontitis / Q000503:physiopathology; D010519:Periodontium / Q000276:immunology / Q000502:physiology; D016133:Polymerase Chain Reaction; D000067996:RAW 264.7 Cells; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: C511592:Aspn protein, mouse; D016326:Extracellular Matrix Proteins; D016328:NF-kappa B; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051550:I-kappa B Kinase
keywords: ECM protein; LPS; extracellular matrix (ECM); inflammatory cytokines; periodontal ligament (PDL); periodontitis