Anti-phosphorylcholine-opsonized low-density lipoprotein promotes rapid production of proinflammatory cytokines by dendritic cells and natural killer cells.
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.
Kikuchi
T
T
Clinical Research Center for Periodontal Diseases, School of Dentistry, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA.
El Shikh
M M
MM
El Sayed
R M
RM
Purkall
D B
DB
Elaasser
M M
MM
Sarraf
A
A
Barbour
S E
SE
Schenkein
H A
HA
Tew
J G
JG
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
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