HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Liu, G. Articles by Abraham, E. Search for Related Content PubMed PubMed Citation Articles by Liu, G. Articles by Abraham, E.

p53 Attenuates Lipopolysaccharide-Induced NF-B Activation and Acute Lung Injury ¹

Department of Medicine, University of Alabama at Birmingham, AL 35294

The transcriptional factor p53 has primarily been characterized for its central role in the regulation of oncogenesis. A reciprocal relationship between the activities of p53 and NF-B has been demonstrated in cancer cells, but there is little information concerning interactions between p53 and NF-B in inflammatory processes. In this study, we found that neutrophils and macrophages lacking p53, i.e., p53^–/–, have elevated responses to LPS stimulation compared with p53^+/+ cells, producing greater amounts of proinflammatory cytokines, including TNF-, IL-6, and MIP-2, and demonstrating enhanced NF-B DNA-binding activity. p53^–/– mice are more susceptible than are p53^+/+ mice to LPS-induced acute lung injury (ALI). The enhanced response of p53^–/– cells to LPS does not involve alterations in intracellular signaling events associated with TLR4 engagement, such as activation of MAPKs, phosphorylation of IB- or the p65 subunit of NF-B, or IB- degradation. Culture of LPS-stimulated neutrophils and macrophages with nutlin-3a, a specific inducer of p53 stabilization, attenuated NF-B DNA-binding activity and production of proinflammatory cytokines. Treatment of mice with nutlin-3a reduced the severity of LPS-induced ALI. These data demonstrate that p53 regulates NF-B activity in inflammatory cells and suggest that modulation of p53 may have potential therapeutic benefits in acute inflammatory conditions, such as ALI.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by a pilot grant to G.L. under National Institutes of Health Grant 5P30DK072482 and National Institutes of Health Grant 5R01HL62221 to E.A.

² Address correspondence and reprint requests to Dr. Edward Abraham, Department of Medicine, University of Alabama at Birmingham, School of Medicine, 420 Boshell Building, 1808 7th Avenue South, Birmingham, AL 35294. E-mail address: eabraham{at}uab.edu

³ Abbreviations used in this paper: ALI, acute lung injury; PAMP, pathogenesis-associated molecular patterns; IKK, IB kinase; BAL, bronchoalveolar lavage; PI, propidium iodide; MPO, myeloperoxidase; ChIP, chromatin immunoprecipitation.

⁴ The online version of this article contains supplemental material.