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Original Article

Ib Kinase Is Essential for Mature B Cell Development and Function

^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
Department of Host Defense, Research Institute for Microbial Disease, Osaka University, Yamadaoka 3-1, Suita, Osaka 565-0871, Japan.81-6-6879-830581-6-6879-8302

sakira{at}biken.osaka-u.ac.jp

IB kinase (IKK) and β phosphorylate IB proteins and activate the transcription factor, nuclear factor (NF)-B. Although both are highly homologous kinases, gene targeting experiments revealed their differential roles in vivo. IKK is involved in skin and limb morphogenesis, whereas IKKβ is essential for cytokine signaling. To elucidate in vivo roles of IKK in hematopoietic cells, we have generated bone marrow chimeras by transferring control and IKK-deficient fetal liver cells. The mature B cell population was decreased in IKK^–/– chimeras. IKK^–/– 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^–/– B cells not only showed impairment of survival and mitogenic responses in vitro, accompanied by decreased, although inducible, NF-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^–/– chimeras. Taken together, these results demonstrate that IKK is critically involved in the prevention of cell death and functional development of mature B cells.

Key Words: gene targeting • B cells • IB kinase • germinal center • nuclear factor B

Abbreviations used in this paper: B6, C57BL/6; BCR, B cell receptor; BM, bone marrow; BrdU, 5-bromo-2'-deoxyuridine; BTK, Bruton's tyrosine kinase; CG, chicken -globulin; FDC, follicular dendritic cell; GC, germinal center; HE, hematoxylin and eosin; HSA, heat stable antigen; IKK, IB kinase; NF, nuclear factor; NP, 4-hydroxy-3-nitro-phenylacetyl; PB, peripheral blood; PNA, peanut agglutinin; RAG, recombination activating gene; tg, transgenic.

© 2001 The Rockefeller University Press

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