IκB kinase α is essential for mature B cell development and function

I kappaB kinase (IKK) alpha and beta phosphorylate I kappaB proteins and activate the transcription factor, nuclear factor (NF)-kappaB. 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 IKK beta 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-kappaB 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.