Arterial Inflammation in Mice Lacking the Interleukin 1 Receptor Antagonist Gene

doi:10.1084/jem.191.2.303

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© The Rockefeller University Press, 0022-1007/2000/1/303/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 2, January 17, 2000 303-312

Original Article

Arterial Inflammation in Mice Lacking the Interleukin 1 Receptor Antagonist Gene

Martin J.H. Nicklin^a, David E. Hughes^b, Jenny L. Barton^a, Jan M. Ure^c, and Gordon W. Duff^a
^a Division of Molecular and Genetic Medicine, University of Sheffield, Royal Hallamshire Hospital, Sheffield S10 2JF, United Kingdom
^b Division of Oncology and Cellular Pathology, University of Sheffield, Royal Hallamshire Hospital, Sheffield S10 2JF, United Kingdom
^c Gene Targeting Laboratory, Centre for Genome Research, University of Edinburgh, Edinburgh EH9 3JQ, United Kingdom

Correspondence to: Martin J.H. Nicklin, Div. of Molecular and Genetic Medicine, University of Sheffield, Sheffield S10 2JF, UK. Tel:44-114-271-3261 Fax:44-114-272-1104 E-mail:m.nicklin{at}sheffield.ac.uk.

Branch points and flexures in the high pressure arterial systemhave long been recognized as sites of unusually high turbulenceand consequent stress in humans are foci for atheroscleroticlesions. We show that mice that are homozygous for a null mutationin the gene encoding an endogenous antiinflammatory cytokine,interleukin 1 receptor antagonist (IL-1ra), develop lethal arterialinflammation involving branch points and flexures of the aortaand its primary and secondary branches. We observe massive transmuralinfiltration of neutrophils, macrophages, and CD4⁺ T cells.Animals appear to die from vessel wall collapse, stenosis, andorgan infarction or from hemorrhage from ruptured aneurysms.Heterozygotes do not die from arteritis within a year of birthbut do develop small lesions, which suggests that a reducedlevel of IL-1ra is insufficient to fully control inflammationin arteries. Our results demonstrate a surprisingly specificrole for IL-1ra in the control of spontaneous inflammation inconstitutively stressed artery walls, suggesting that expressionof IL-1 is likely to have a significant role in signaling arterywall damage.

Key Words: interleukin 1, vasculitis, aorta, arteritis, chronic disease

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