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(Circulation. 2005;112:1323-1331.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Involvement of Tumor Necrosis Factor- in the Development of T Cell–Dependent Aortitis in Interleukin-1 Receptor Antagonist–Deficient Mice

Taizo Matsuki, PhD; Kikuo Isoda, MD, PhD; Reiko Horai, PhD; Akiko Nakajima, MSc; Yoshifusa Aizawa, MD, PhD; Kazuo Suzuki, PhD; Fumitaka Ohsuzu, MD, PhD; Yoichiro Iwakura, DSc

From the Center for Experimental Medicine (T.M., R.H., A.N., Y.I.), Institute of Medical Science, University of Tokyo, Tokyo; the First Department of Internal Medicine (K.I., F.O.), National Defense Medical College, Saitama; the Department of Biological Functions and Medical Control, Cardiovascular and Vital Control (Y.A.), Niigata Graduate School of Medical and Dental Sciences, Niigata; and the Department of Bioactive Molecules (K.S.), National Institute of Infectious Diseases, Tokyo, Japan.

Correspondence to Yoichiro Iwakura, DSc, Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Shirokanedai 4-6-1, Minato-ku, Tokyo 108-8639, Japan. E-mail iwakura{at}ims.u-tokyo.ac.jp

Received November 15, 2004; de novo received March 16, 2005; revision received May 25, 2005; accepted June 1, 2005;

Background— Interleukin-1 receptor antagonist–deficient (IL-1Ra^–/–) mice on the BALB/c background spontaneously develop inflammatory arthropathy that resembles rheumatoid arthritis in humans. These mice also frequently develop aortitis at the root of the aorta, but the mechanism underlying the development of this disease has not been completely elucidated.

Methods and Results— Using IL-1Ra^–/– mice (backcrossed 8 generations to the BALB/c background) and wild-type mice, we studied the histopathology and examined the immunologic mechanisms involved in the development of aortic inflammation by cell transplantation experiments. Half of the IL-1Ra^–/– mice developed aortitis at the root of the aorta, with massive infiltration of macrophages and monocytes and loss of elastic lamellae in the aortic media. Left ventricular hypertrophy and mild aortic stenosis were also shown by transthoracic echocardiography. Transplantation of T cells from IL-1Ra^–/– mice induced aortitis in recipient nu/nu mice. Bone marrow cell transplants from IL-1Ra^–/– mice also induced aortitis in irradiated wild-type recipient mice. Furthermore, tumor necrosis factor (TNF)- deficiency completely suppressed the development of aortitis in IL-1Ra^–/– mice, whereas IL-6 deficiency did not affect pathology.

Conclusions— These observations suggest that IL-1Ra deficiency in T cells activates them excessively, resulting in the development of aortitis in IL-1Ra^–/– mice in a TNF-–dependent manner.

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