Inhibition of B cell receptor-mediated apoptosis by IFN.
IFNs are a family of cytokines that are involved in the regulation of immune and inflammatory responses. Clinical use of IFN-alpha/beta encompasses treatment for a variety of diseases; however, prolonged exposure to IFN-alpha/beta results in elevated levels of autoreactive Abs. In this study, we investigated the potential of IFNs to modulate apoptotic signals in B cells. We demonstrate that IFN-alpha or IFN-beta inhibit Ag receptor-mediated apoptosis in a dose-dependent manner. Inhibition of phosphatidylinositol 3' (PI3)-kinase did not abolish the effect of IFN, indicating that the antiapoptotic mechanism is PI3-kinase- and protein kinase B/Akt-independent. Instead, IFN-alpha and IFN-beta, but not IFN-gamma, significantly increase the levels of the survival protein Bcl-2, and to a lesser extent, Bcl-xL expression. Thus, IFN-alpha/beta-mediated inhibition of B cell Ag receptor-triggered apoptosis may offer a model for the process that leads to the escape of self-reactive B cells from negative selection and consequently results in autoantibody production.
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Department of Biology, University of California, San Diego, Cancer Center, La Jolla 92093, USA.
David
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D000730:Androstadienes / Q000494:pharmacology; D000888:Antibodies, Anti-Idiotypic / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D002051:Burkitt Lymphoma; D019013:CD40 Antigens / Q000378:metabolism / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016898:Interferon-alpha / Q000494:pharmacology*; D016899:Interferon-beta / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000077191:Wortmannin; D051020:bcl-X Protein
D000730:Androstadienes; D000888:Antibodies, Anti-Idiotypic; D019013:CD40 Antigens; D004791:Enzyme Inhibitors; D019833:Genistein; D007166:Immunosuppressive Agents; D016898:Interferon-alpha; D016899:Interferon-beta; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell; D020123:Sirolimus; D000077191:Wortmannin; D051020:bcl-X Protein; C494811:BCL2L1 protein, human; C044203:anti-IgM