Abstract
The role of apoptosis in regulating the course of intracellular microbial infection is not well understood. We studied the relationship between apoptotic regulation and bacillus Calmette-Guérin (BCG) treatment in murine peritoneal exudate macrophages (PEM) and the J774 macrophage cell line. In both PEM and J774 cells, mRNA expression of the anti-apoptotic gene, A1, was selectively induced by BCG treatment as compared with other bcl2 family members (bcl-w, bcl-2, bcl-xl, bcl-xs, bax, bak, bad). In PEM, A1 expression was maximal by 8 h postinfection and was abrogated by the proteasomal inhibitor MG-132. The induction was independent of protein synthesis as well as the p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways and did not require live organism. Three genes encoding closely related isoforms of A1 were all expressed; however, the A1-a isoform displayed the greatest fold induction in PEM. BCG-induced A1 expression was associated with protection of host macrophages from NO-mediated apoptosis in both PEM and J774 cells. BCG-mediated protection was abrogated in PEM derived from A1-a(-/-) mice, indicating a requirement of A1-a for survival of inflammatory macrophages.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / immunology*
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BCG Vaccine / immunology*
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Cell Line
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Cells, Cultured
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Cytotoxicity, Immunologic / genetics
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Cytotoxicity, Immunologic / immunology
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology*
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Female
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Homeodomain Proteins*
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Macrophages / cytology*
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Macrophages / immunology
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Macrophages / metabolism*
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Macrophages / microbiology
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Macrophages, Peritoneal / cytology
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Macrophages, Peritoneal / immunology
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Macrophages, Peritoneal / metabolism
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Macrophages, Peritoneal / microbiology
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Mice
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Mice, Inbred BALB C
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Mice, Transgenic
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Minor Histocompatibility Antigens
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Nitric Oxide / pharmacology*
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Protein Isoforms / biosynthesis
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Protein Isoforms / physiology
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Proto-Oncogene Proteins c-bcl-2 / physiology*
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Replication Protein C
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Repressor Proteins*
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Saccharomyces cerevisiae Proteins*
Substances
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BCG Vaccine
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BCL2-related protein A1
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DNA-Binding Proteins
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Homeodomain Proteins
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MATA1 protein, S cerevisiae
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Minor Histocompatibility Antigens
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Protein Isoforms
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Proto-Oncogene Proteins c-bcl-2
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Repressor Proteins
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Saccharomyces cerevisiae Proteins
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Nitric Oxide
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Replication Protein C