title: Interleukin-1 receptor antagonist (IL-1RN) genotype modulates the replicative capacity of human endothelial cells.
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.
authors.affiliation: Cardiovascular Research Group, Clinical Sciences, University of Sheffield, Northern General Hospital, Sheffield, S5 7AU, UK.
authors.forename: Rachael M
authors.initials: RM
authors.lastname: Dewberry
authors.forename: David C
authors.initials: DC
authors.lastname: Crossman
authors.forename: Sheila E
authors.initials: SE
authors.lastname: Francis
mesh_terms: D000483:Alleles; D017209:Apoptosis / Q000235:genetics; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D004730:Endothelium, Vascular / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D019394:Ki-67 Antigen / Q000032:analysis; D012795:Sialoglycoproteins / Q000235:genetics* / Q000494:pharmacology; D016615:Telomere / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D019394:Ki-67 Antigen; D012795:Sialoglycoproteins