IKKβ Is Required for Peripheral B Cell Survival and Proliferation

Abstract

NF-κB activity in mammalian cells is regulated through the IκB kinase (IKK) complex, consisting of two catalytic subunits (IKKα and IKKβ) and a regulatory subunit (IKKγ). Targeted deletion of Ikkβ results in early embryonic lethality, thus complicating the examination of IKKβ function in adult tissues. Here we describe the role of IKKβ in B lymphocytes made possible by generation of a mouse strain that expresses a conditional Ikkβ allele. We find that the loss of IKKβ results in a dramatic reduction in all peripheral B cell subsets due to associated defects in cell survival. IKKβ-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-κB signaling pathway. These findings are consistent with a failure to mount effective Ab responses to T cell-dependent and independent Ags. Thus, IKKβ provides a requisite role in B cell activation and maintenance and thus is a key determinant of humoral immunity.

NF-κB and the immune response

“…As mentioned above, p50 and p50/pRelA double knockout B cells are deficient in responses to TI stimulation. Likewise, IKKb-deficient B cells fail to mount TI or TD responses (Li et al, 2003). These IKKb-deficient B cells also exhibit increased spontaneous apoptosis, suggesting that NF-kB is important in survival of B cells.…”

“…Most likely this was due to the loss of signaling to NF-kB in these cells because loss of IKKb, NEMO or components of the CBM complex in mature B cells also results in a complete loss of peripheral B cells (Pasparakis et al, 2002;Li et al, 2003;Thome, 2004).…”

IKKβ in postnatal perichondrium remotely controls endochondral ossification of the growth plate through downregulation of MCP-5

“…Ikkβ F/F mouse was described previously. 10 Ikkβ F/F mice were crossed with Prx1-Cre mice (purchased from Jackson Laboratories, Bar Harbor, ME, USA), Col1a1-Cre mice (obtained from Dr. S Kato, with permission from Dr. G Karsenty, Columbia University Medical Center, New York, NY, USA) and Col2a1-Cre mice (obtained from Dr. N Chano, Shiga University of Medical Science, Shiga, Japan). We genotyped offsprings by PCR using the following primers: Cre-for, 5′-TCCAATTTACTGACCGTACACCAA-3′; Cre-rev, 5′-CCTGATCCTGGCA ATTTCGGCTA-3′; IKKβ-flox-for, 5′-GTCATTTCCACAGCCCTGTGA-3′; IKKβ-flox-rev, 5′-CCTTGTCCTATAGAAGCACAAC-3′.…”

“…The PCR product size was 220 bp (wild-type allele) and 310 bp (floxed allele). 10 Histology and histomorphometry. Hind limbs from 2-week-old Ikkβ cKO and Ikkβ F/F control mice were dissected and used for paraffin and methylmethacrylate (MMA) embedding with and without decalcification, respectively.…”

“…5,6 Because mice deficient for the gene encoding IKKβ die in midgestation, [7][8][9] to investigate the function of IKKβ in vivo in tissue-and stage-specific settings, mice with a floxed Ikkβ allele have been generated. 10,11 The skeleton is an organ that not only supports and protects the body, but is also involved in other functions via communications with other organs. These communications render unanticipated complexities to skeletal patterning and to the specification/differentiation of skeletal cells during development.…”