Regulation of developing B cell survival by RelA-containing NF-kappa B complexes

J Immunol. 2003 Oct 15;171(8):3963-9. doi: 10.4049/jimmunol.171.8.3963.


Mice deficient in the RelA (p65) subunit of NF-kappaB die during embryonic development. Fetal liver (FL) hemopoietic precursors from these mice were used to generate RelA-deficient lymphocytes by adoptive transfer into lethally irradiated mature lymphocyte-deficient recombination-activating gene-1(-/-) mice. Strikingly, RelA(-/-) lymphocyte generation was greatly diminished compared with that of RelA(+/+) lymphocytes. The most dramatic reduction was noticed in the numbers of developing B cells, which were considerably increased when RelA(-/-) FL cells that were also TNFR1 deficient were used. The role of RelA was further investigated in FL-derived developing B cells in vitro. Our results show that RelA is a major component of constitutive and TNF-alpha-induced kappaB site-binding activity in developing B cells, and provide evidence for a direct role of TNF-alpha in killing RelA(-/-) B cells. The absence of RelA significantly reduced mRNA expression of the antiapoptotic genes cellular FLICE-inhibitory protein and Bcl-2. Retroviral transduction of RelA(-/-) B cells with either cFLIP or Bcl-2 significantly reduced TNF-alpha killing. Together, these results indicate that RelA plays a crucial role in regulating developing B cell survival by inhibiting TNF-alpha cytotoxicity.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / physiology
  • Apoptosis / genetics
  • Apoptosis / immunology
  • B-Lymphocyte Subsets / cytology*
  • B-Lymphocyte Subsets / immunology
  • B-Lymphocyte Subsets / metabolism*
  • Binding Sites / genetics
  • Binding Sites / immunology
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / physiology
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Cell Survival / genetics
  • Cell Survival / immunology
  • Cells, Cultured
  • Cytotoxicity, Immunologic / genetics
  • Genetic Vectors
  • Homeodomain Proteins / genetics
  • Intracellular Signaling Peptides and Proteins*
  • Mice
  • Mice, Knockout
  • NF-kappa B / deficiency
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • NF-kappa B / physiology*
  • Protein Subunits / deficiency
  • Protein Subunits / genetics
  • Protein Subunits / physiology*
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Proto-Oncogene Proteins c-bcl-2 / physiology
  • Receptors, Tumor Necrosis Factor / deficiency
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / physiology
  • Receptors, Tumor Necrosis Factor, Type I
  • Retroviridae / genetics
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / toxicity


  • Antigens, CD
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carrier Proteins
  • Cflar protein, mouse
  • Homeodomain Proteins
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • Protein Subunits
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • RAG-1 protein