Abstract
Although IFN-alpha was reported to promote the survival of peripheral B-lymphocytes via the PI3-kinase-Akt pathway, the triggered signalling pathways involved in the protection of B cell from apoptosis need to be clarified. Using flow cytometry and western blot analysis, we have found that type 1 IFNs (IFN-alpha/beta) protect human B cells in culture from spontaneous apoptosis and from apoptosis mediated by anti-CD95 agonist, in a dose- and time-dependant manner. IFN-alpha/beta-mediated anti-apoptotic effect on human B cells was totally abrogated by blockade of IFNR1 chain. Our data indicate that PI3Kdelta, Rho-A, NFkappaB and Bcl-2/Bcl(XL) are active downstream of IFN receptors and are the major effectors of IFN-alpha/beta-rescued B cells from apoptosis. Furthermore, immunohistochemical results show marked reduction in numbers of CD20 positive B cell in both spleen and Peyer's patches from mice treated with anti-IFNR1 blocking antibody compared with control group. Moreover, ultrastructural observations of these organs show an obvious increase in apoptotic cells from mice treated with anti-IFNR1 blocking antibody. Our results provide more details about the triggered signalling pathways and the phosphorylation cascade which are involved in the protection of B cell from apoptosis after treatment with IFN-alpha/beta.
Copyright 2010 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenine / analogs & derivatives
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Adenine / pharmacology
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Amides / pharmacology
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Animals
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Antibodies, Blocking / pharmacology
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Apoptosis / drug effects*
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Apoptosis / immunology
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B-Lymphocytes / drug effects*
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B-Lymphocytes / immunology
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B-Lymphocytes / metabolism
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B-Lymphocytes / pathology
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Cells, Cultured
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Class I Phosphatidylinositol 3-Kinases
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Gene Expression Regulation
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Humans
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Imidazoles / pharmacology
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Immunologic Memory
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Interferon Type I / administration & dosage
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Interferon Type I / pharmacology*
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Lymphocyte Subsets / drug effects*
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Lymphocyte Subsets / immunology
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Lymphocyte Subsets / metabolism
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Lymphocyte Subsets / pathology
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Mice
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NF-kappa B / antagonists & inhibitors
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Oncogene Protein v-akt / antagonists & inhibitors
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Peptides / pharmacology
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Pyridines / pharmacology
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Quinazolines / pharmacology
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Receptors, Interferon / immunology
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Recombinant Proteins
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Signal Transduction / drug effects*
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Signal Transduction / immunology
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bcl-X Protein / metabolism
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rho-Associated Kinases / antagonists & inhibitors
Substances
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Amides
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Antibodies, Blocking
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IC 87114
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Imidazoles
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Interferon Type I
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NF-kappa B
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Peptides
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins c-bcl-2
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Pyridines
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Quinazolines
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Receptors, Interferon
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Recombinant Proteins
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SN50 peptide
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bcl-X Protein
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Y 27632
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Class I Phosphatidylinositol 3-Kinases
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Pik3cd protein, mouse
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Oncogene Protein v-akt
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rho-Associated Kinases
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Adenine
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SB 203580