Involvement of tumor necrosis factor-alpha in the development of T cell-dependent aortitis in interleukin-1 receptor antagonist-deficient mice.
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.


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)-alpha 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-alpha-dependent manner.
Matsuki
Taizo
T
Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Shirokanedai 4-6-1, Tokyo 108-8639, Japan.
Isoda
Kikuo
K
Horai
Reiko
R
Nakajima
Akiko
A
Aizawa
Yoshifusa
Y
Suzuki
Kazuo
K
Ohsuzu
Fumitaka
F
Iwakura
Yoichiro
Y
D000818:Animals; D001025:Aortitis / Q000209:etiology*; D001168:Arthritis / Q000209:etiology; D001794:Blood Pressure; D001854:Bone Marrow Cells / Q000502:physiology; D006332:Cardiomegaly / Q000209:etiology; D017690:Cell Transplantation; D005260:Female; D006339:Heart Rate; D053590:Interleukin 1 Receptor Antagonist Protein; D015850:Interleukin-6 / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012795:Sialoglycoproteins / Q000172:deficiency / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D015850:Interleukin-6; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha