© 2000 American Heart Association, Inc.
Vascular Biology |
Interleukin-1 Receptor Antagonist Expression in Human Endothelial Cells and Atherosclerosis
From Cardiovascular Medicine, Division of Clinical Sciences, Northern General Hospital, and the Division of Molecular and Genetic Medicine (H.H.), University of Sheffield, Sheffield, UK.
Correspondence to Dr Sheila E. Francis, Cardiovascular Medicine, Division of Clinical Sciences, Northern General Hospital, Sheffield S5 7AU, UK. E-mail s.francis{at}sheffield.ac.uk
Abstract—The
proinflammatory cytokine interleukin (IL)-1 is expressed mainly
within the endothelium of atherosclerotic plaques and
may be linked with inflammatory mechanisms of atherogenesis. IL-1
action is complex and regulated in part by its naturally occurring
inhibitor, the IL-1 receptor antagonist
(IL-1ra). Therefore, we studied differential and specific isoform
expression of IL-1ra in the endothelium of diseased
coronary arteries and in endothelial cells
(ECs) stimulated under defined conditions. In view of an association
with IL-1ra gene (IL-1RN) polymorphism, the influence of
endothelial cell genotype at IL-1RN on IL-1ra
protein production was also examined. Secreted IL-1ra and
intracellular IL-1ra mRNAs were detected by semiquantitative reverse
transcription–polymerase chain reaction in human atherosclerotic and
dilated cardiomyopathic coronary arteries;
protein expression appeared increased in atherosclerotic compared with
dilated cardiomyopathic arteries, where IL-1ra appeared
to be confined to the endothelium. Only intracellular
IL-1ra type I mRNA was detected in human umbilical vein ECs (HUVECs)
and human coronary artery ECs (HCAECs) when they were
stimulated with bacterial lipopolysaccharide/phorbol
myristate acetate and transforming growth factor-ß. IL-1ß
and IL-1
were without effect. IL-1ra protein was detected in HUVECs
(intracellular IL-1ra), HCAECs (intracellular IL-1ra), and human
coronary artery smooth muscle cells (intracellular IL-1ra) by
immunoprecipitation and Western blot. IL-1ra was detected in
HUVEC cell lysates by ELISA and appeared to be influenced by the
genotype of the IL-1RN variable number tandem repeat, an
86-bp repeat polymorphism in intron 2 of the IL-1ra gene, with
lower levels of IL-1ra produced by IL-1RN allele 2–containing
cells (ratio of IL-1ra to total protein: for 1,1 homozygotes,
1.38±0.28x10-9 [n=15]; for 1,2
heterozygotes, 0.81±0.17x10-9 [n=8]; and
for 2,2 homozygotes, 0.63±0.19x10-9 [n=5];
P<0.05 compared with 1,1 homozygotes). This is the
first demonstration of IL-1ra in human diseased arteries, stimulated
HUVECs, and HCAECs and indicates the endothelial cell
as an important source. Endothelial IL-1ra
production may be controlled by the endothelial
IL-1RN genotype. These data further support the role of the
IL-1 system of cytokines in the pathogenesis of
atherosclerosis.
Key Words: interleukin-1 receptor antagonist • endothelium • inflammation • human coronary arteries
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