Epigenetic regulation of dendritic cell differentiation and function by oxidized phospholipids.
Dendritic cells (DCs) are the key cell type in the regulation of an adaptive immune response. Under inflammatory conditions monocytes can give rise to immunostimulatory DCs, depending on microenvironmental stimuli. Here we show that oxidized phospholipids (Ox-Pls), which are generated during inflammatory reactions, dysregulate the differentiation of DCs. DCs generated in the presence of Ox-Pls up-regulated the typical DC marker DC-SIGN but did not express CD1a, CD1b, and CD1c. These DCs generated in the presence of Ox-Pls had a substantially diminished T cell-stimulating capacity after stimulation with Toll-like receptor ligands. Toll-like receptor ligand-induced production of interleukin-12 also was strongly diminished, whereas induction of CD83 was not altered. In addition, we found that Ox-Pls strongly inhibit inflammatory stimuli-induced phosphorylation of histone H3, a key step of interleukin-12 production, yet leaving activation of nuclear factor-kappaB unaltered. Taken together, Ox-Pls present during differentiation yielded DCs with a reduced capacity to become immunostimulatory mature DCs. Furthermore, the presence of Ox-Pls blocked histone modifications required for full activation of DCs. Therefore, inflammation-derived Ox-Pls control DC functions in part by epigenetic mechanisms.
Blüml
Stephan
S
Institute of Immunology, Medical University of Vienna, Vienna, Austria. stephan.blueml@meduniwien.ac.at
Zupkovitz
Gordin
G
Kirchberger
Stefanie
S
Seyerl
Maria
M
Bochkov
Valery N
VN
Stuhlmeier
Karl
K
Majdic
Otto
O
Zlabinger
Gerhard J
GJ
Seiser
Christian
C
Stöckl
Johannes
J
D015703:Antigens, CD / Q000235:genetics; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D044127:Epigenesis, Genetic; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics; D018664:Interleukin-12 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010713:Phosphatidylcholines / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000097802:CD83 Antigen
D015703:Antigens, CD; D006657:Histones; D007136:Immunoglobulins; D018664:Interleukin-12; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010713:Phosphatidylcholines; D000097802:CD83 Antigen; C472349:oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine