Deficiency of interleukin-1 receptor antagonist induces aortic valve disease in BALB/c mice.
OBJECTIVE
Interleukin-1 receptor antagonist (IL-1Ra), one of the most important antiinflammatory cytokines, is crucial for homeostasis of the immune system. However, the role of IL-1Ra in aortic valve stenosis (AS) remains poorly understood [corrected].


RESULTS
IL-1Ra-deficient (IL-1Ra(-/-)) mice on the BALB/c background showed increased aortic valve leaflet thickness compared to wild-type mice at the age of 12 weeks (P<0.001). We used peripheral T-cell transplantation to examine the role of T cells in the development of AS. T cells from IL-1Ra(-/-) but not from wild-type mice induced increased aortic valve thickness in nu/nu mice. Moreover, IL-1Ra(-/-) T cells produced much higher levels of tumor necrosis factor (TNF)-alpha in culture supernatants after anti-CD3 antibody stimulation compared to wild-type mice (P<0.001). Finally, we studied the role of TNF-alpha in the development of AS in IL-1Ra(-/-) mice by generating double-gene-deficient (TNF-alpha(-/-)/IL-1Ra(-/-)) mice. Interestingly, TNF-alpha(-/-)/IL-1Ra(-/-) mice did not have AS.


CONCLUSIONS
IL-1Ra deficiency in inflammatory cells induced aortic valve inflammation and TNF-alpha participates importantly in the development of AS in IL-1Ra(-/-) mice.
Isoda
Kikuo
K
Internal Medicine I, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama, 359-8513, Japan. isoda@ndmc.ac.jp
Matsuki
Taizo
T
Kondo
Harumi
H
Iwakura
Yoichiro
Y
Ohsuzu
Fumitaka
F
D000367:Age Factors; D000375:Aging; D000818:Animals; D001021:Aortic Valve / Q000000981:diagnostic imaging / Q000276:immunology*; D001024:Aortic Valve Stenosis / Q000000981:diagnostic imaging / Q000235:genetics / Q000276:immunology*; D016026:Bone Marrow Transplantation; D017252:CD3 Complex / Q000378:metabolism; D002478:Cells, Cultured; D015150:Echocardiography, Doppler; D053590:Interleukin 1 Receptor Antagonist Protein / Q000172:deficiency* / Q000235:genetics; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000172:deficiency / Q000235:genetics
D017252:CD3 Complex; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D008055:Lipids; D014409:Tumor Necrosis Factor-alpha