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(Circulation Research. 2003;92:1285.)
© 2003 American Heart Association, Inc.

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Interleukin-1 Receptor Antagonist (IL-1RN) Genotype Modulates the Replicative Capacity of Human Endothelial Cells

Rachael M. Dewberry, David C. Crossman, Sheila E. Francis

From the Cardiovascular Research Group, Clinical Sciences (North), University of Sheffield, Northern General Hospital, Sheffield, UK.

Correspondence to Sheila Francis, PhD, Cardiovascular Research Group, Clinical Sciences (North), University of Sheffield, Northern General Hospital, Sheffield, S5 7AU, UK. E-mail s.francis{at}sheffield.ac.uk

Abstract

Endothelial cells (ECs) undergo a finite number of cell divisions before growth arrest or replicative senescence, modulated in part by the proinflammatory cytokine, interleukin-1 (IL-1). IL-1 and its family members are expressed in human atherosclerotic vessels, mainly in the endothelium. EC replicative senescence and IL-1 have been associated with atherosclerosis. Genetic variants at the IL-1 locus have been associated with a variety of coronary phenotypes. In this study, we examined the relationship between the interleukin-1 receptor antagonist variable number tandem repeat allele 2 (IL-1RN*2*2) and EC replicative capacity. A significant decrease in EC cumulative population doublings (CPDs) was associated with the rare allele (IL-1RN*2*2) at IL-1RN, 8.56±0.97 (n=7) versus 13.14±1.00 (IL-1RN*1*1, n=20), P=0.0118. Proliferation of IL-1RN*2*2 ECs detected by Ki67 expression was also significantly reduced particularly at later passage, passage 6: 21.76±0.93% (n=6) versus 48.10±8.81% (IL-1RN*1*1, n=7) (P=0.0323) and passage 8: 22.48±3.08% (n=6) versus 42.29±3.06% (IL-1RN*1*1, n=7) (P=0.0028). IL-1RN*2 carriage was associated with increased numbers of senescent ECs. Basal apoptosis, telomerase activity, and telomere length were not different with respect to IL-1RN genotype. Addition of exogenous IL-1ra (1 ng/mL) increased CPDs in a number of human umbilical vein endothelial cell cultures and increased proliferating cells from 12.11±1.21% to 27.82±2.82% (P=0.0216, IL-1RN*2*2, passage 8, n=2). These data suggest genetic control of EC proliferation and life span by the IL-1 locus and imply that IL-1ra may have a function connected with EC growth.

Key Words: interleukin-1 receptor antagonist • endothelial cells • proliferation

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