© 1999 American Heart Association, Inc.
Original Contributions |
High-Density Lipoproteins Differentially Modulate Cytokine-Induced Expression of E-Selectin and Cyclooxygenase-2
From the BHF Cardiovascular Medicine Unit (G.W.C., H.Y., B.O., D.O.H.), National Heart and Lung Institute, the Section on Clinical Pharmacology (G.T.), Imperial College School of Medicine, the MRC Lipid Team (S.N.), Hammersmith Hospital, the Kennedy Institute of Rheumatology (J.S., S.H.R.), and the Department of Cardiovascular Biochemistry (N.E.M.), St Bartholomews and the Royal School of Medicine and Dentistry, London, UK.
Correspondence to G.W. Cockerill, BHF Cardiovascular Medicine, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK. E-mail gcockeri{at}rpms.ac.uk
Abstract—Atherogenesis is
a multifactorial chronic inflammatory disease in which low plasma
levels of HDLs are a strong predictor of the condition. Although the
mechanism of protection by HDLs is not precisely known, HDLs have been
shown to influence many of the events involved in the development of
atherosclerosis. Previously we have shown that HDLs
inhibited the cytokine-induced expression of adhesion
molecules (E-selectin, VCAM-1, and ICAM-1) by
endothelial cells (ECs). As the complete
transcriptional regulation of all 3 genes requires the NF-
B family
of transcription factors, we examined the effect of HDLs on activation
of NF-B. We also investigated the effect of HDLs on 2 other
cytokine-induced genes, granulocyte-macrophage
colony-stimulating factor (GM-CSF) and
cyclooxygenase (Cox-2; prostaglandin
H2 synthase, EC 0.1.14.99.1). E-selectin expression
in response to tumor necrosis factor-
(TNF) was, as expected,
inhibited in ECs that had been preincubated with HDLs. However, the
level of secretion of GM-CSF in the same cultures was no different from
control. In a similar manner, although HDLs had no effect on
steady-state mRNA levels of GM-CSF, the levels of E-selectin were
significantly inhibited by HDLs. In transient cotransfection
experiments we found that HDLs inhibited the
cytokine-induced expression of a reporter gene driven by
the E-selectin proximal promoter (-383 to 80) but had no effect
on the expression of a reporter gene driven under the control of the
proximal promoter of GM-CSF (-627 to 28). As would be predicted from
this differential response, HDLs did not influence the nuclear
translocation or DNA binding of NF-B, or alter the kinetics of
degradation and resynthesis of the inhibitory protein
IB. We found that HDLs synergized with cytokine to
enhance the expression of Cox-2 and induce the synthesis of its main EC
product, prostacyclin (PGI2), a potent
inhibitor of platelet and leukocyte functions. In
conclusion, HDL induces an antiinflammatory phenotype in
cytokine-induced ECs, synergizing with cytokine to
induce elevation of Cox-2 in addition to inhibiting adhesion molecule
expression. Our studies show that these differential effects are
mediated in a manner that is likely to be independent of NF-B
per se.
Key Words: inflammation • coronary artery disease • prostacyclin • granulocyte-macrophage colony-stimulating factor
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