title: Conditional Deletion of NF-κB-Inducing Kinase (NIK) in Adult Mice Disrupts Mature B Cell Survival and Activation.
abstract: NF-κB-inducing kinase (NIK) is a primary regulator of the noncanonical NF-κB signaling pathway, which plays a vital role downstream of BAFF, CD40L, lymphotoxin, and other inflammatory mediators. Germline deletion or inactivation of NIK in mice results in the defective development of B cells and secondary lymphoid organs, but the role of NIK in adult animals has not been studied. To address this, we generated mice containing a conditional allele of NIK. Deletion of NIK in adult mice results in decreases in B cell populations in lymph nodes and spleen, similar to what is observed upon blockade of BAFF. Consistent with this, B cells from mice in which NIK is acutely deleted fail to respond to BAFF stimulation in vitro and in vivo. In addition, mice with induced NIK deletion exhibit a significant decrease in germinal center B cells and serum IgA, which is indicative of roles for NIK in additional pathways beyond BAFF signaling. Our conditional NIK-knockout mice may be broadly useful for assessing the postdevelopmental and cell-specific roles of NIK and the noncanonical NF-κB pathway in mice.
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080; hansb@gene.com lawrenw@amgen.com.
authors.forename: Hans D
authors.initials: HD
authors.lastname: Brightbill
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080;
authors.forename: Janet K
authors.initials: JK
authors.lastname: Jackman
authors.affiliation: Department of Translational Immunology, Genentech Inc., South San Francisco, CA 94080;
authors.forename: Eric
authors.initials: E
authors.lastname: Suto
authors.affiliation: Department of Pathology, Genentech Inc., South San Francisco, CA 94080; and.
authors.forename: Heather
authors.initials: H
authors.lastname: Kennedy
authors.affiliation: Department of Pathology, Genentech Inc., South San Francisco, CA 94080; and.
authors.forename: Charles
authors.initials: C
authors.lastname: Jones
authors.affiliation: Department of Pathology, Genentech Inc., South San Francisco, CA 94080; and.
authors.forename: Sreedevi
authors.initials: S
authors.lastname: Chalasani
authors.affiliation: Department of Translational Immunology, Genentech Inc., South San Francisco, CA 94080;
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080.
authors.forename: Lucinda
authors.initials: L
authors.lastname: Tam
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080.
authors.forename: Meron
authors.initials: M
authors.lastname: Roose-Girma
authors.affiliation: Department of Translational Immunology, Genentech Inc., South San Francisco, CA 94080;
authors.forename: Mercedesz
authors.initials: M
authors.lastname: Balazs
authors.affiliation: Department of Pathology, Genentech Inc., South San Francisco, CA 94080; and.
authors.forename: Cary D
authors.initials: CD
authors.lastname: Austin
authors.affiliation: Department of Translational Immunology, Genentech Inc., South San Francisco, CA 94080;
authors.forename: Wyne P
authors.initials: WP
authors.lastname: Lee
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080; hansb@gene.com lawrenw@amgen.com.
authors.forename: Lawren C
authors.initials: LC
authors.lastname: Wu
mesh_terms: D000818:Animals; D053264:B-Cell Activating Factor / Q000235:genetics*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D018095:Germ-Line Mutation; D051550:I-kappa B Kinase / Q000378:metabolism; D007070:Immunoglobulin A / Q000097:blood; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D052003:NF-kappa B p52 Subunit / Q000096:biosynthesis* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D017384:Sequence Deletion; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000166:cytology; D013629:Tamoxifen / Q000494:pharmacology; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D053264:B-Cell Activating Factor; D051550:I-kappa B Kinase; D007070:Immunoglobulin A; D052003:NF-kappa B p52 Subunit; D017346:Protein Serine-Threonine Kinases; D013629:Tamoxifen; D000097782:NF-kappaB-Inducing Kinase; C505720:Tnfsf13b protein, mouse; C496564:Chuk protein, mouse