Oxidized phospholipids negatively regulate dendritic cell maturation induced by TLRs and CD40.
Maturation of dendritic cells (DCs) induced by pathogen-derived signals via TLRs is a crucial step in the initiation of an adaptive immune response and therefore has to be well controlled. In this study, we demonstrate that oxidized phospholipids (ox-PLs), which are generated during infections, apoptosis, and tissue damage, interfere with DC activation, preventing their maturation. ox-PLs blocked TLR-3- and TLR-4-mediated induction of the costimulatory molecules CD40, CD80, CD83, and CD86, the cytokines IL-12 and TNF, as well as lymphocyte stimulatory capacity. CD40 and TLR-2-mediated cytokine production was also inhibited, whereas up-regulation of costimulatory molecules via these receptors was not affected by ox-PLs. Thus, formation of ox-PLs during the course of an inflammatory response may represent a negative-feedback loop preventing excessive and sustained immune reactions through regulating DC maturation.
Institute of Immunology, Medical University of Vienna, Medical University of Vienna, Vienna, Austria.
Stefan
S
Blüml
Stefanie
S
Kirchberger
Valery N
VN
Bochkov
Gerhard
G
Krönke
Karl
K
Stuhlmeier
Otto
O
Majdic
Gerhard J
GJ
Zlabinger
Walter
W
Knapp
Bernd R
BR
Binder
Johannes
J
Stöckl
Norbert
N
Leitinger
D001483:Base Sequence; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000494:pharmacology; D002454:Cell Differentiation; D016207:Cytokines / Q000096:biosynthesis; D018076:DNA, Complementary / Q000235:genetics; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D005246:Feedback; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction; D010457:Peptidoglycan / Q000494:pharmacology; D010713:Phosphatidylcholines / Q000494:pharmacology; D010743:Phospholipids / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D011070:Poly I-C / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D019013:CD40 Antigens; D016207:Cytokines; D018076:DNA, Complementary; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010457:Peptidoglycan; D010713:Phosphatidylcholines; D010743:Phospholipids; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495344:TLR3 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C472349:oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine; D023201:CD40 Ligand; D011070:Poly I-C