Essential role of IkappaB kinase alpha in thymic organogenesis required for the establishment of self-tolerance.
IkappaB kinase (IKK) alpha exhibits diverse biological activities through protein kinase-dependent and -independent functions, the former mediated predominantly through a noncanonical NF-kappaB activation pathway. The in vivo function of IKKalpha, however, still remains elusive. Because a natural strain of mice with mutant NF-kappaB-inducing kinase (NIK) manifests autoimmunity as a result of disorganized thymic structure with abnormal expression of Rel proteins in the thymic stroma, we speculated that the NIK-IKKalpha axis might constitute an essential step in the thymic organogenesis that is required for the establishment of self-tolerance. An autoimmune disease phenotype was induced in athymic nude mice by grafting embryonic thymus from IKKalpha-deficient mice. The thymic microenvironment that caused autoimmunity in an IKKalpha-dependent manner was associated with defective processing of NF-kappaB2, resulting in the impaired development of thymic epithelial cells. Thus, our results demonstrate a novel function for IKKalpha in thymic organogenesis for the establishment of central tolerance that depends on its protein kinase activity in cooperation with NIK.
Department of Obstetrics and Gynecology, Institute of Health Biosciences, University of Tokushima Graduate School, Japan.
Dan
D
Kinoshita
Fumiko
F
Hirota
Tsuneyasu
T
Kaisho
Michiyuki
M
Kasai
Keisuke
K
Izumi
Yoshimi
Y
Bando
Yasuhiro
Y
Mouri
Akemi
A
Matsushima
Shino
S
Niki
Hongwei
H
Han
Kiyotaka
K
Oshikawa
Noriyuki
N
Kuroda
Masahiko
M
Maegawa
Minoru
M
Irahara
Kiyoshi
K
Takeda
Shizuo
S
Akira
Mitsuru
M
Matsumoto
D000818:Animals; D005786:Gene Expression Regulation; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D020572:Oncogene Proteins v-rel / Q000378:metabolism; D038081:Organogenesis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017634:Self Tolerance / Q000276:immunology*; D013950:Thymus Gland / Q000196:embryology* / Q000201:enzymology / Q000276:immunology*; D000097782:NF-kappaB-Inducing Kinase
D051550:I-kappa B Kinase; D016328:NF-kappa B; D020572:Oncogene Proteins v-rel; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase