This Article Full Text Full Text (PDF) All Versions of this Article: 108/5/516    most recent 01.CIR.0000085567.18648.21v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Isoda, K. Articles by Ohsuzu, F. Search for Related Content PubMed PubMed Citation Articles by Isoda, K. Articles by Ohsuzu, F. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH Related Collections Growth factors/cytokines

(Circulation. 2003;108:516.)
© 2003 American Heart Association, Inc.

Brief Rapid Communications

Deficiency of Interleukin-1 Receptor Antagonist Promotes Neointimal Formation After Injury

Kikuo Isoda, MD, PhD; Masaru Shiigai, MD; Norio Ishigami, MD; Taizo Matsuki, BSc; Reiko Horai, PhD; Kenichirou Nishikawa, MD; Masatoshi Kusuhara, MD, PhD; Yasuhiro Nishida, MD, PhD; Yoichiro Iwakura, DSc; Fumitaka Ohsuzu, MD, PhD

From the First Department of Internal Medicine (K.I., M.S., N.I., K.N., M.K., F.O.), and Department of Physiology II (Y.N.), National Defense Medical College, Tokorozawa, Japan; and the Center for Experimental Medicine, Institute of Medical Science, University of Tokyo (T.M., R.H., Y.I.), Tokyo, Japan.

Correspondence to Kikuo Isoda, MD, PhD, First Department of Internal Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama, 359-8513, Japan. E-mail isoda{at}me.ndmc.ac.jp

Received March 12, 2003; de novo received April 28, 2003; revision received June 12, 2003; accepted June 13, 2003.

Background— The cytokine interleukin (IL)-1 is an important mediator of inflammation and cardiovascular disease. Activity of this cytokine is modulated endogenously via the IL-1 receptor antagonist (IL-1Ra). The role of IL-1Ra in neointima formation after injury, however, is poorly understood.

Methods and Results— Using IL-1Ra–deficient (IL-1Ra^-/-; backcrossed 8 generations into the C57BL/6J background) and wild-type (IL-1Ra^+/+) mice, we investigated neointimal formation 3 weeks after femoral artery injury induced by an external vascular cuff model. Intima and media thicknesses were measured, and the intima/media ratio was calculated. The mean intimal thickness and the intima/media ratio of IL-1Ra^-/- mice increased by 249% (31.8±2.9 µm [n=10] versus 9.1±0.7 µm [n=10]; P<0.0001) and 257% (2.5±0.2 versus 0.7±0.1; P<0.0001), respectively, compared with IL-1Ra^+/+ mice. No significant differences were observed in the medial thickness. Control immunostaining for IL-1Ra in injured vessels localized IL-1ß and the endogenous inhibitor in the endothelium and inflammatory cells of the adventitia in IL-1Ra^+/+ but not IL-1Ra^-/- mice.

Conclusions— The absence of IL-1Ra promotes neointimal formation in mice after injury. These results suggest that endogenous IL-1Ra may suppress other occlusive vascular responses to injury, such as atherosclerosis and restenosis after angioplasty.

Key Words: genes • inflammation • interleukins

This article has been cited by other articles:

				N. Yajima, M. Takahashi, H. Morimoto, Y. Shiba, Y. Takahashi, J. Masumoto, H. Ise, J. Sagara, J. Nakayama, S. Taniguchi, et al. Critical Role of Bone Marrow Apoptosis-Associated Speck-Like Protein, an Inflammasome Adaptor Molecule, in Neointimal Formation After Vascular Injury in Mice Circulation, June 17, 2008; 117(24): 3079 - 3087. [Abstract] [Full Text] [PDF]

				W. F. Fearon and D. T. Fearon Inflammation and Cardiovascular Disease: Role of the Interleukin-1 Receptor Antagonist Circulation, May 20, 2008; 117(20): 2577 - 2579. [Full Text] [PDF]

				H. Loppnow, K. Werdan, and M. Buerke Invited review: Vascular cells contribute to atherosclerosis by cytokine- and innate-immunity-related inflammatory mechanisms Innate Immunity, April 1, 2008; 14(2): 63 - 87. [Abstract] [PDF]

				Hardev Ramandeep Singh Girn, S. Ahilathirunayagam, A. I. D. Mavor, and S. Homer-Vanniasinkam Reperfusion Syndrome: Cellular Mechanisms of Microvascular Dysfunction and Potential Therapeutic Strategies Vascular and Endovascular Surgery, September 1, 2007; 41(4): 277 - 293. [Abstract] [PDF]

				K. Schultz, V. Murthy, J. B. Tatro, and D. Beasley Endogenous interleukin-1{alpha} promotes a proliferative and proinflammatory phenotype in human vascular smooth muscle cells Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2927 - H2934. [Abstract] [Full Text] [PDF]

				B. B. Worrall, T. G. Brott, R. D. Brown Jr, W. M. Brown, S. S. Rich, S. Arepalli, F. Wavrant-De Vrieze, J. Duckworth, A. B. Singleton, J. Hardy, et al. IL1RN VNTR Polymorphism in Ischemic Stroke: Analysis in 3 Populations Stroke, April 1, 2007; 38(4): 1189 - 1196. [Abstract] [Full Text] [PDF]

				M. Rahmani, R. P. Cruz, D. J. Granville, and B. M. McManus Allograft Vasculopathy Versus Atherosclerosis Circ. Res., October 13, 2006; 99(8): 801 - 815. [Abstract] [Full Text] [PDF]

				J. Chamberlain, D. Evans, A. King, R. Dewberry, S. Dower, D. Crossman, and S. Francis Interleukin-1{beta} and Signaling of Interleukin-1 in Vascular Wall and Circulating Cells Modulates the Extent of Neointima Formation in Mice Am. J. Pathol., April 1, 2006; 168(4): 1396 - 1403. [Abstract] [Full Text] [PDF]

				A. C. Morton, N. D. Arnold, J. Gunn, R. Varcoe, S. E. Francis, S. K. Dower, and D. C. Crossman Interleukin-1 receptor antagonist alters the response to vessel wall injury in a porcine coronary artery model Cardiovasc Res, December 1, 2005; 68(3): 493 - 501. [Abstract] [Full Text] [PDF]

				E. W. Raines and N. Ferri Thematic Review Series: The Immune System and Atherogenesis. Cytokines affecting endothelial and smooth muscle cells in vascular disease J. Lipid Res., June 1, 2005; 46(6): 1081 - 1092. [Abstract] [Full Text] [PDF]

				Y. R. Su, D. E. Dove, A. S. Major, A. H. Hasty, B. Boone, M. F. Linton, and S. Fazio Reduced ABCA1-Mediated Cholesterol Efflux and Accelerated Atherosclerosis in Apolipoprotein E-Deficient Mice Lacking Macrophage-Derived ACAT1 Circulation, May 10, 2005; 111(18): 2373 - 2381. [Abstract] [Full Text] [PDF]

				H. Chi, E. Messas, R. A. Levine, D. T. Graves, and S. Amar Interleukin-1 Receptor Signaling Mediates Atherosclerosis Associated With Bacterial Exposure and/or a High-Fat Diet in a Murine Apolipoprotein E Heterozygote Model: Pharmacotherapeutic Implications Circulation, September 21, 2004; 110(12): 1678 - 1685. [Abstract] [Full Text] [PDF]

				K. Isoda, S. Sawada, N. Ishigami, T. Matsuki, K. Miyazaki, M. Kusuhara, Y. Iwakura, and F. Ohsuzu Lack of Interleukin-1 Receptor Antagonist Modulates Plaque Composition in Apolipoprotein E-Deficient Mice Arterioscler. Thromb. Vasc. Biol., June 1, 2004; 24(6): 1068 - 1073. [Abstract] [Full Text] [PDF]