title: Signaling pathways and genes that inhibit pathogen-induced macrophage apoptosis--CREB and NF-kappaB as key regulators.
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.
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California-San Diego, La Jolla, CA 92093, USA.
authors.forename: Jin Mo
authors.initials: JM
authors.lastname: Park
authors.forename: Florian R
authors.initials: FR
authors.lastname: Greten
authors.forename: Athena
authors.initials: A
authors.lastname: Wong
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Westrick
authors.forename: J Simon C
authors.initials: JS
authors.lastname: Arthur
authors.forename: Kinya
authors.initials: K
authors.lastname: Otsu
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoffmann
authors.forename: Marc
authors.initials: M
authors.lastname: Montminy
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
mesh_terms: D000818:Animals; D000881:Anthrax / Q000276:immunology; D017209:Apoptosis / Q000235:genetics* / Q000276:immunology; D001408:Bacillus anthracis / Q000276:immunology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology*; D020287:In Situ Nick-End Labeling; D008264:Macrophages / Q000276:immunology / Q000382:microbiology*; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D017396:Plasminogen Activator Inhibitor 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology; D051197:Toll-Like Receptor 4; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D016328:NF-kappa B; D017396:Plasminogen Activator Inhibitor 2; D011971:Receptors, Immunologic; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D048051:p38 Mitogen-Activated Protein Kinases