Anti-phosphorylcholine-opsonized low-density lipoprotein promotes rapid production of proinflammatory cytokines by dendritic cells and natural killer cells.
BACKGROUND AND 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. MATERIAL AND 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. CONCLUSION: 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.
Kikuchi, T; El Shikh, MM; El Sayed, RM; Purkall, DB; Elaasser, MM; Sarraf, A; Barbour, SE; Schenkein, HA; Tew, JG
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