OXIDIZED LIPIDS
We previously have demonstrated that oxidized 1-palmitoyl-2-arachidonoyl-
sn-glycero-3-phosphorylcholine
(OxPAPC), a component of minimally modified low density lipoprotein (MM-LDL),
activates endothelial cells to
bind monocytes. 1-Palmitoyl-2- (5-oxovaleroyl)- sn-glycero-3-phosphorylcholine
(POVPC) and 1- palmitoyl-2-
glutaroyl- sn-glycero-3-phosphorylcholine (PGPC), which are present in OxPAPC,
MM-LDL, and atherosclerotic
lesions, were shown to have a major role in the activation of endothelial cells.
We now demonstrate that thesetwo highly similar molecules have dramatically different
effects on leukocyte
endothelial interactions. POVPC is
a potent regulator of monocyte-specific endothelial interactions. Treatment of
endothelial cells with POVPCincreased monocyte binding by inducing the surface
expression of the connecting
segment 1 domain offibronectin; no increase in neutrophil binding was observed.
In addition, POVPC
strongly inhibitedlipopolysaccharide-mediated induction of neutrophil binding
and expression of
E-selectin protein and mRNA.This inhibition was mediated by a protein kinase
A-dependent pathway, resulting
in down-regulation of NF-
kappaB-dependent transcription. In contrast, PGPC induced both monocyte and neutrophil
binding and
expression of E-selectin and vascular cell adhesion molecule 1. We present evidence
to suggest that the two
phospholipids act by different novel receptors present in Xenopus laevis oocytes
and that POVPC, but not
PGPC, stimulates a cAMP-mediated pathway. At concentrations equal to that present
in MM-LDL, the effect of
POVPC dominates and inhibits PGPC-induced neutrophil binding and E-selectin expression
in endothelial cells.
In summary, our data provide evidence that both POVPC and PGPC are important
regulators of leukocyte-
endothelial interactions and that POVPC may play a dominant role in a number
of chronic inflammatory
processes where oxidized phospholipids are known to be present.
Structurally similar oxidized phospholipids differentially regulate endothelial
binding of monocytes and
neutrophils.
REFERENCES
(1999). Leitinger, N., T.R. Tyner, L.
Oslund, C. Rizza, G. Subbanagounder, H. Lee, P.T. Shih,
N. Mackman, G. Tigyi, M.C. Territo, J.A. Berliner, and D.K.
Vora.Structurally similar oxidized phospholipids differentially regulate
endothelial
binding of monocytes and neutrophils.
Proc Natl Acad Sci. Oct 12;96(21):12010-5. [PubMed]
