Regulation of cell survival during B lymphopoiesis: apoptosis and Bcl-2/Bax content of precursor B cells in bone marrow of mice with altered expression of IL-7 and recombinase-activating gene-2

J Immunol. 1999 Feb 15;162(4):1931-40.

Abstract

B cell development in mouse bone marrow depends critically upon IL-7. To examine the possible in vivo trophic role of IL-7, we have quantitated apoptosis and Bcl-2 family proteins in populations of phenotypically defined B lineage cells in IL-7-deficient and IL-7-overexpressing mice. Using immunofluorescence labeling, multiparameter flow cytometry, and a short-term culture assay, we show that the apoptotic rates of precursor B cells, but not of more mature B cells, are enhanced by IL-7 gene deletion, associated with increased intracellular content of Bax and decreased Bcl-2, while, conversely, an IL-7 transgene suppresses precursor B cell apoptosis and produces low Bax and high Bcl-2 levels. During normal B cell development, high Bax/Bcl-2 ratios characterize cells undergoing greatest apoptotic cell death. Pro-B cells in RAG-2-/- mice, all destined to abort, show elevated Bax levels and Bax/Bcl-2 ratios. By comparison with the elevated rate of pro-B cell apoptosis in RAG-2-/- mice, provisional estimates have been made for the fraction of pro-B cells undergoing apoptosis in normal mice (70%), IL-7-/- mice (85%), and IL-7 transgenic mice (35%). The results demonstrate that IL-7 strongly promotes in vivo cell survival and maintains antiapoptotic Bcl-2/Bax ratios during the development of precursor B cells in mouse bone marrow.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / immunology*
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / metabolism
  • Bone Marrow Cells / cytology*
  • Bone Marrow Cells / metabolism
  • Cell Survival / genetics
  • Cell Survival / immunology
  • Cells, Cultured
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics*
  • Hematopoiesis / genetics
  • Hematopoiesis / immunology
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / metabolism
  • Interleukin-7 / biosynthesis
  • Interleukin-7 / deficiency
  • Interleukin-7 / genetics*
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred DBA
  • Mice, Knockout
  • Mice, Transgenic
  • Proto-Oncogene Proteins / biosynthesis
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Transposases / genetics
  • bcl-2-Associated X Protein

Substances

  • Bax protein, mouse
  • DNA-Binding Proteins
  • Interleukin-7
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Rag2 protein, mouse
  • V(D)J recombination activating protein 2
  • bcl-2-Associated X Protein
  • Transposases