Signaling pathways and genes that inhibit pathogen-induced macrophage apoptosis--CREB and NF-kappaB as key regulators.
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.
Park
Jin Mo
JM
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California-San Diego, La Jolla, CA 92093, USA.
Greten
Florian R
FR
Wong
Athena
A
Westrick
Randal J
RJ
Arthur
J Simon C
JS
Otsu
Kinya
K
Hoffmann
Alexander
A
Montminy
Marc
M
Karin
Michael
M
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
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