title: The major outer membrane protein of a periodontopathogen induces IFN-beta and IFN-stimulated genes in monocytes via lipid raft and TANK-binding kinase 1/IFN regulatory factor-3.
abstract: Surface molecules of pathogens play an important role in stimulating host immune responses. Elucidation of the signaling pathways activated by critical surface molecules in host cells provides insight into the molecular pathogenesis resulting from bacteria-host interactions. MspTL is the most abundant outer membrane protein of Treponema lecithinolyticum, which is associated with periodontitis, and induces expression of a variety of proinflammatory factors. Although bacteria and bacterial components like LPS and flagellin are known to induce IFN-beta, induction by bacterial surface proteins has not been reported. In the present study, we investigated MspTL-mediated activation of signaling pathways stimulating up-regulation of IFN-beta and IFN-stimulated genes in a human monocytic cell line, THP-1 cells, and primary cultured human gingival fibroblasts. MspTL treatment of the cells induced IFN-beta and the IFN-stimulated genes IFN-gamma-inducible protein-10 (IP-10) and RANTES. A neutralizing anti-IFN-beta Ab significantly reduced the expression of IP-10 and RANTES, as well as STAT-1 activation, which was also induced by MspTL. Experiments using specific small interfering RNA showed that MspTL activated TANK-binding kinase 1 (TBK1), but not inducible IkappaB kinase (IKKi). MspTL also induced dimerization of IFN regulatory factor-3 (IRF-3) and translocation into the nucleus. The lipid rapid-disrupting agents methyl-beta-cyclodextrin, nystatin, and filipin inhibited the MspTL internalization and cellular responses, demonstrating that lipid raft activation was a prerequisite for MspTL cellular signaling. Our results demonstrate that MspTL, the major outer protein of T. lecithinolyticum, induced IFN-beta expression and subsequent up-regulation of IP-10 and RANTES via TBK1/IRF-3/STAT-1 signaling secondary to lipid raft activation.
authors.affiliation: Department of Oral Microbiology and Immunology, Seoul National University, Seoul, Republic of Korea.
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Joong Su
authors.initials: JS
authors.lastname: Kim
authors.forename: Hye-Kyoung
authors.initials: HK
authors.lastname: Jun
authors.forename: Hae-Ri
authors.initials: HR
authors.lastname: Lee
authors.forename: Daesil
authors.initials: D
authors.lastname: Lee
authors.forename: Bong-Kyu
authors.initials: BK
authors.lastname: Choi
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics / Q000276:immunology; D001426:Bacterial Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000235:genetics; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000502:physiology; D019281:Dimerization; D005347:Fibroblasts / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D015964:Gene Expression Regulation, Bacterial / Q000276:immunology*; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism / Q000502:physiology*; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D021962:Membrane Microdomains / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology; D009000:Monocytes / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology; D010518:Periodontitis / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D018272:Porins / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014208:Treponema / Q000276:immunology* / Q000472:pathogenicity; D014211:Treponemal Infections / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D001426:Bacterial Proteins; C114753:CXCL10 protein, human; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D050838:Interferon Regulatory Factor-3; D018272:Porins; C099361:major outer sheath protein, Treponema; D016899:Interferon-beta; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human