title: Anti-phosphorylcholine-opsonized low-density lipoprotein promotes rapid production of proinflammatory cytokines by dendritic cells and natural killer cells.
abstract: OBJECTIVE
  Epidemiological and animal studies suggest that periodontal infections increase atherosclerosis risk. Periodontitis patients have elevated levels of anti-phosphorylcholine (anti-PC) reactive not only with numerous periodontal organisms but also with minimally modified low-density lipoprotein (mmLDL). Dendritic cells (DCs) reside in arterial walls and accumulate in atherosclerotic lesions. The ability of anti-PC to bind mmLDL prompted the hypothesis that opsonized mmLDL would stimulate DCs and enhance the production of proinflammatory cytokines that promote atherogenic plaque development.
  
  
  METHODS
  Monocyte-derived DCs (mDCs) were generated using granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4, then stimulated with mmLDL or with anti-PC-opsonized mmLDL. The anti-PC effect was determined using flow cytometry, cofocal microscopy and cytokine assays. The production of CD83, IL-12p35 mRNA, IL-12p40 mRNA, IL-12p70 and IL-10 by DCs was monitored.
  
  
  RESULTS
  Dendritic cells stimulated with mmLDL expressed little CD83 and produced little IL-12p70. However, anti-PC-opsonized mmLDL enhanced DC maturation, as indicated by upregulated CD83 and rapid (≤ 48 h) production of IL-12p70 if a source of interferon-γ (IFN-γ) was available. In leukocyte cultures, natural killer (NK) cells rapidly produced IFN-γ (≤ 48 h) when interacting with IL-12-producing DCs activated by anti-PC-opsonized mmLDL. Moreover, IFN-γ promoted DC IL-12 responses that were further augmented when mmLDL was opsonized with anti-PC.
  
  
  CONCLUSIONS
  Minimally modified LDL-stimulated DCs and NK cells were mutually stimulatory, with DC IL-12p70 needed by NK cells and with NK cell IFN-γ needed by DCs. Moreover, production of these proinflammatory cytokines was markedly enhanced when LDL was opsonized by anti-PC. In short, the data suggest that the elevated anti-PC levels in periodontitis patients could promote a mechanism that facilitates atherosclerosis.
authors.affiliation: Clinical Research Center for Periodontal Diseases, School of Dentistry, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Kikuchi
authors.forename: M M
authors.initials: MM
authors.lastname: El Shikh
authors.forename: R M
authors.initials: RM
authors.lastname: El Sayed
authors.forename: D B
authors.initials: DB
authors.lastname: Purkall
authors.forename: M M
authors.initials: MM
authors.lastname: Elaasser
authors.forename: A
authors.initials: A
authors.lastname: Sarraf
authors.forename: S E
authors.initials: SE
authors.lastname: Barbour
authors.forename: H A
authors.initials: HA
authors.lastname: Schenkein
authors.forename: J G
authors.initials: JG
authors.lastname: Tew
mesh_terms: D016976:Aggregatibacter actinomycetemcomitans; D000704:Analysis of Variance; D000906:Antibodies; D015703:Antigens, CD / Q000096:biosynthesis; D050197:Atherosclerosis / Q000209:etiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D053765:Interleukin-12 Subunit p35 / Q000096:biosynthesis; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D009895:Opsonin Proteins / Q000276:immunology*; D010767:Phosphorylcholine / Q000276:immunology*; D016966:Porphyromonas gingivalis; D018709:Statistics, Nonparametric; D000097802:CD83 Antigen
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D016207:Cytokines; D007136:Immunoglobulins; D018836:Inflammation Mediators; D007371:Interferon-gamma; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D008077:Lipoproteins, LDL; D008562:Membrane Glycoproteins; D009895:Opsonin Proteins; D010767:Phosphorylcholine; D000097802:CD83 Antigen