title: p53 Integrates host defense and cell fate during bacterial pneumonia.
abstract: Cancer and infection are predominant causes of human mortality and derive, respectively, from inadequate genomic and host defenses against environmental agents. The transcription factor p53 plays a central role in human tumor suppression. Despite its expression in immune cells and broad responsiveness to stressors, it is virtually unknown whether p53 regulates host defense against infection. We report that the lungs of naive p53(-/-) mice display genome-wide induction of NF-κB response element-enriched proinflammatory genes, suggestive of type 1 immune priming. p53-null and p53 inhibitor-treated mice clear Gram-negative and -positive bacteria more effectively than controls after intrapulmonary infection. This is caused, at least in part, by cytokines produced by an expanded population of apoptosis-resistant, TLR-hyperresponsive alveolar macrophages that enhance airway neutrophilia. p53(-/-) neutrophils, in turn, display heightened phagocytosis, Nox-dependent oxidant generation, degranulation, and bacterial killing. p53 inhibition boosts bacterial killing by mouse neutrophils and oxidant generation by human neutrophils. Despite enhanced bacterial clearance, infected p53(-/-) mice suffer increased mortality associated with aggravated lung injury. p53 thus modulates host defense through regulating microbicidal function and fate of phagocytes, revealing a fundamental link between defense of genome and host during environmental insult.
authors: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
authors: Jennifer H
authors: JH
authors: Madenspacher
authors: Kathleen M
authors: KM
authors: Azzam
authors: Kymberly M
authors: KM
authors: Gowdy
authors: Kenneth C
authors: KC
authors: Malcolm
authors: Jerry A
authors: JA
authors: Nick
authors: Darlene
authors: D
authors: Dixon
authors: Jim J
authors: JJ
authors: Aloor
authors: David W
authors: DW
authors: Draper
authors: John J
authors: JJ
authors: Guardiola
authors: Maria
authors: M
authors: Shatz
authors: Daniel
authors: D
authors: Menendez
authors: Julie
authors: J
authors: Lowe
authors: Jun
authors: J
authors: Lu
authors: Pierre
authors: P
authors: Bushel
authors: Leping
authors: L
authors: Li
authors: B Alex
authors: BA
authors: Merrick
authors: Michael A
authors: MA
authors: Resnick
authors: Michael B
authors: MB
authors: Fessler
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D016678:Genome / Q000235:genetics; D054884:Host-Pathogen Interactions / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000276:immunology; D007958:Leukocyte Count; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D009569:Nitric Oxide / Q000096:biosynthesis; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D016019:Survival Analysis; D051193:Toll-Like Receptors / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*
chemical_list: D000890:Anti-Infective Agents; D016207:Cytokines; D016328:NF-kappa B; D051193:Toll-Like Receptors; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide
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