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.
Kinoshita
Dan
D
Department of Obstetrics and Gynecology, Institute of Health Biosciences, University of Tokushima Graduate School, Japan.
Hirota
Fumiko
F
Kaisho
Tsuneyasu
T
Kasai
Michiyuki
M
Izumi
Keisuke
K
Bando
Yoshimi
Y
Mouri
Yasuhiro
Y
Matsushima
Akemi
A
Niki
Shino
S
Han
Hongwei
H
Oshikawa
Kiyotaka
K
Kuroda
Noriyuki
N
Maegawa
Masahiko
M
Irahara
Minoru
M
Takeda
Kiyoshi
K
Akira
Shizuo
S
Matsumoto
Mitsuru
M
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