B-cell receptor and Fas-mediated signals for life and death.

A series of B-cell lymphoma lines with an immature phenotype has been used as a model system to study molecular events associated with receptor ligation induced death. B-cell receptor (BCR) cross-linking with antibodies to membrane IgM (but not with anti IgD) induces c-Myc downregulation via nuclear factor kappaB inactivation and p27(Kip1) accumulation in these B lymphomas. Anti-mu-treated cells then undergo G1 arrest and die by apoptosis independent of Fas. Steroids and retinoids similarly downregulate c-Myc and induce apoptosis in these B cells and synergize with anti-mu. Rescue from apoptosis induced by anti-mu or steroids occurs with T-cell signals, like CD40L, or a broad-range caspase inhibitor, but only CD40L prevents the loss of c-Myc, p27 accumulation and growth arrest. Both IgM and IgD signaling lead to modulation of phosphatidylinositol 3-kinase (PI3K) signals, including the activation of p70(S6K), but this pathway recovers under anti-IgD treatment. Blockade of the PI3K pathway augments anti-mu-induced death and converts anti-delta to an apoptotic signal. Resistance to Fas-mediated death may be an important factor in B-cell transformation in vivo. Many of our panel of lymphomas are insensitive to Fas-mediated death signals, although all can form a death-inducing signaling complex (DISC). Additional studies suggest that some lymphomas can be blocked at the DISC complex by anti-apoptotic proteins, whereas others are inhibited downstream of caspase 8 activation. Anti-Ig treatment of a Fas-sensitive line, A20.2J, activated a number of genes whose products may block apoptosis proximally (like FLICE-inhibitory protein (FLIP1)) or at late points, such as bcl-2-family members. Our data suggest that B lymphomas develop multiple pathways of resistance to Fas-mediated signals during lymphomagenesis, in part via signaling through the BCR.
AuthorsG B Carey, D Donjerković, C M Mueller, S Liu, J A Hinshaw, L Tonnetti, W Davidson, D W Scott
JournalImmunological reviews (Immunol Rev) Vol. 176 Pg. 105-15 (Aug 2000) ISSN: 0105-2896 [Print] DENMARK
PMID11043771 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., Review)
Chemical References
  • Antigens, CD95
  • Immunoglobulin D
  • Immunoglobulin M
  • Receptors, Antigen, B-Cell
  • Animals
  • Antigens, CD95 (metabolism)
  • Apoptosis
  • B-Lymphocytes (cytology, immunology, metabolism)
  • Cell Division
  • Humans
  • Immunoglobulin D (metabolism)
  • Immunoglobulin M (metabolism)
  • Lymphoma, B-Cell (immunology, metabolism, pathology)
  • Receptors, Antigen, B-Cell (metabolism)
  • Signal Transduction
  • Tumor Cells, Cultured

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