Abstract
Certain microbes evade host innate immunity by killing activated macrophages with the help of virulence factors that target prosurvival pathways. For instance, infection of macrophages with the TLR4-activating bacterium Bacillus anthracis triggers an apoptotic response due to inhibition of p38 MAP kinase activation by the bacterial-produced lethal toxin. Other pathogens induce macrophage apoptosis by preventing activation of NF-kappaB, which depends on IkappaB kinase beta (IKKbeta). To better understand how p38 and NF-kappaB maintain macrophage survival, we searched for target genes whose products prevent TLR4-induced apoptosis and a p38-dependent transcription factor required for their induction. Here we describe key roles for transcription factor CREB, a target for p38 signaling, and the plasminogen activator 2 (PAI-2) gene, a target for CREB, in maintenance of macrophage survival.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Anthrax / immunology
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Apoptosis / genetics*
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Apoptosis / immunology
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Bacillus anthracis / immunology
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Cyclic AMP Response Element-Binding Protein / genetics
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Cyclic AMP Response Element-Binding Protein / immunology
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Cyclic AMP Response Element-Binding Protein / metabolism*
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Gene Expression Regulation / immunology*
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In Situ Nick-End Labeling
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Macrophages / immunology
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Macrophages / microbiology*
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Mice
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NF-kappa B / genetics
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NF-kappa B / immunology
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NF-kappa B / metabolism*
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Oligonucleotide Array Sequence Analysis
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Plasminogen Activator Inhibitor 2 / genetics
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Plasminogen Activator Inhibitor 2 / immunology
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Plasminogen Activator Inhibitor 2 / metabolism
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Receptors, Immunologic / immunology
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Receptors, Immunologic / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / genetics*
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Signal Transduction / immunology
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Toll-Like Receptor 4
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Transcription, Genetic
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p38 Mitogen-Activated Protein Kinases / immunology
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Cyclic AMP Response Element-Binding Protein
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NF-kappa B
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Plasminogen Activator Inhibitor 2
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Receptors, Immunologic
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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p38 Mitogen-Activated Protein Kinases