The Journal of Experimental Medicine
Keystone Symposia
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Published online 12 February 2001.
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© The Rockefeller University Press, 0022-1007/2001/2/417/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 4, February 19, 2001 417-426

Original Article

I{kappa}B Kinase {alpha} Is Essential for Mature B Cell Development and Function

Tsuneyasu Kaishoa,b,d, Kiyoshi Takedaa,d, Tohru Tsujimurac, Taro Kawaia,d, Fumiko Nomuraa,d, Nobuyuki Teradac, and Shizuo Akiraa,d
a Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
b Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
c Department of Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
d Core Research for Evolution Science and Technology (CREST), Japan Science and Technology Corporation, Tokyo 101-0062, Japan

Correspondence to: Shizuo Akira, Department of Host Defense, Research Institute for Microbial Disease, Osaka University, Yamadaoka 3-1, Suita, Osaka 565-0871, Japan. Tel:81-6-6879-8302 Fax:81-6-6879-8305 E-mail:sakira{at}biken.osaka-u.ac.jp.

I{kappa}B kinase (IKK) {alpha} and ß phosphorylate I{kappa}B proteins and activate the transcription factor, nuclear factor (NF)-{kappa}B. Although both are highly homologous kinases, gene targeting experiments revealed their differential roles in vivo. IKK{alpha} is involved in skin and limb morphogenesis, whereas IKKß is essential for cytokine signaling. To elucidate in vivo roles of IKK{alpha} in hematopoietic cells, we have generated bone marrow chimeras by transferring control and IKK{alpha}-deficient fetal liver cells. The mature B cell population was decreased in IKK{alpha}-/- chimeras. IKK{alpha}-/- chimeras also exhibited a decrease of serum immunoglobulin basal level and impaired antigen-specific immune responses. Histologically, they also manifested marked disruption of germinal center formation and splenic microarchitectures that depend on mature B cells. IKK{alpha}-/- B cells not only showed impairment of survival and mitogenic responses in vitro, accompanied by decreased, although inducible, NF-{kappa}B activity, but also increased turnover rate in vivo. In addition, transgene expression of bcl-2 could only partially rescue impaired B cell development in IKK{alpha}-/- chimeras. Taken together, these results demonstrate that IKK{alpha} is critically involved in the prevention of cell death and functional development of mature B cells.

Key Words: gene targeting, B cells, I{kappa}B kinase {alpha}, germinal center, nuclear factor {kappa}B


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