IKK beta is required for peripheral B cell survival and proliferation.
NF-kappaB activity in mammalian cells is regulated through the IkappaB kinase (IKK) complex, consisting of two catalytic subunits (IKKalpha and IKKbeta) and a regulatory subunit (IKKgamma). Targeted deletion of Ikkbeta results in early embryonic lethality, thus complicating the examination of IKKbeta function in adult tissues. Here we describe the role of IKKbeta in B lymphocytes made possible by generation of a mouse strain that expresses a conditional Ikkbeta allele. We find that the loss of IKKbeta results in a dramatic reduction in all peripheral B cell subsets due to associated defects in cell survival. IKKbeta-deficient B cells are also impaired in mitogenic responses to LPS, anti-CD40, and anti-IgM, indicating a general defect in the ability to activate the canonical NF-kappaB signaling pathway. These findings are consistent with a failure to mount effective Ab responses to T cell-dependent and independent Ags. Thus, IKKbeta provides a requisite role in B cell activation and maintenance and thus is a key determinant of humoral immunity.
Li
Zhi-Wei
ZW
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, Cancer Center, University of California-San Diego, La Jolla, CA 92093, USA.
Omori
Sidne A
SA
Labuda
Tord
T
Karin
Michael
M
Rickert
Robert C
RC
D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics; D000955:Antigens, T-Independent / Q000008:administration & dosage / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D006241:Haptens / Q000008:administration & dosage / Q000276:immunology; D051550:I-kappa B Kinase; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D019426:Integrases / Q000235:genetics; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008221:Lymphoid Tissue / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008231:Lymphopenia / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008934:Mitogens / Q000494:pharmacology; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014301:Trinitrobenzenes / Q000008:administration & dosage / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics
D018941:Antigens, CD19; D000955:Antigens, T-Independent; D006241:Haptens; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008934:Mitogens; D014301:Trinitrobenzenes; D014764:Viral Proteins; C038600:trinitrophenyl-ovalbumin; D010047:Ovalbumin; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; C045073:Cre recombinase; D019426:Integrases