QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Research Data All Versions of this Article: gad.1467606v1 20/22/3174    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lu, J.-Y. Articles by Schneider, R. J. Search for Related Content PubMed PubMed Citation Articles by Lu, J.-Y. Articles by Schneider, R. J. Social Bookmarking                   What's this?

Endotoxic shock in AUF1 knockout mice mediated by failure to degrade proinflammatory cytokine mRNAs

Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA

Excessive production of proinflammatory cytokines, particularly tumor necrosis factor- (TNF) and interleukin-1 (IL-1), plays a critical role in septic shock induced by bacterial endotoxin (endotoxemia). Precise control of cytokine expression depends on rapid degradation of cytokine mRNAs, mediated by an AU-rich element (ARE) in the 3' noncoding region and by interacting ARE-binding proteins, which control the systemic inflammatory response. To understand the function of the ARE-binding protein AUF1, we developed an AUF1 knockout mouse. We show that AUF1 normally functions to protect against the lethal progression of endotoxemia. Upon endotoxin challenge, AUF1 knockout mice display symptoms of severe endotoxic shock, including vascular hemorrhage, intravascular coagulation, and high mortality, resulting from overproduction of TNF and IL-1. Overexpression of these two cytokines is specific, and shown to result from an inability to rapidly degrade these mRNAs in macrophages following induction. Neutralizing antibodies to TNF and IL-1 protect AUF1 knockout mice against lethal endotoxic shock. These and other data describe a novel post-transcriptional mechanism whereby AUF1 acts as a crucial attenuator of the inflammatory response, promoting the rapid decay of selective proinflammatory cytokine mRNAs following endotoxin activation. Defects in the AUF1 post-transcriptionally controlled pathway may be involved in human inflammatory disease.

[Keywords: AU-rich element; ARE; AUF1; mRNA decay; endotoxic shock; cytokines]

Received July 11, 2006; revised version accepted September 25, 2006.

² Present address: BCMM 231, Howard Hughes Medical Institute, Yale University School of Medicine, 295 Congress Ave, New Haven, CT 06536, USA.

³ Corresponding author.

E-MAIL Robert.schneider{at}med.nyu.edu; FAX (212) 263-8276.

Supplemental material is available at http://www.genesdev.org.

Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1467606

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				K. S. Sinsimer, F. M. Gratacos, A. M. Knapinska, J. Lu, C. D. Krause, A. V. Wierzbowski, L. R. Maher, S. Scrudato, Y. M. Rivera, S. Gupta, et al. Chaperone Hsp27, a Novel Subunit of AUF1 Protein Complexes, Functions in AU-Rich Element-Mediated mRNA Decay Mol. Cell. Biol., September 1, 2008; 28(17): 5223 - 5237. [Abstract] [Full Text] [PDF]

				C. Lee, A. Gyorgy, D. Maric, N. Sadri, R. J. Schneider, J. L. Barker, M. Lawson, and D. V. Agoston Members of the NuRD Chromatin Remodeling Complex Interact with AUF1 in Developing Cortical Neurons Cereb Cortex, April 15, 2008; (2008) bhn051v1. [Abstract] [Full Text] [PDF]

				S. Datta, R. Biswas, M. Novotny, P. G. Pavicic Jr., T. Herjan, P. Mandal, and T. A. Hamilton Tristetraprolin Regulates CXCL1 (KC) mRNA Stability J. Immunol., February 15, 2008; 180(4): 2545 - 2552. [Abstract] [Full Text] [PDF]

				T. A. Hamilton, M. Novotny, S. Datta, P. Mandal, J. Hartupee, J. Tebo, and X. Li Chemokine and chemoattractant receptor expression: post-transcriptional regulation J. Leukoc. Biol., August 1, 2007; 82(2): 213 - 219. [Abstract] [Full Text] [PDF]

				E. J. Fialcowitz-White, B. Y. Brewer, J. D. Ballin, C. D. Willis, E. A. Toth, and G. M. Wilson Specific Protein Domains Mediate Cooperative Assembly of HuR Oligomers on AU-rich mRNA-destabilizing Sequences J. Biol. Chem., July 20, 2007; 282(29): 20948 - 20959. [Abstract] [Full Text] [PDF]

				K. S. A. Khabar Rapid transit in the immune cells: the role of mRNA turnover regulation J. Leukoc. Biol., June 1, 2007; 81(6): 1335 - 1344. [Abstract] [Full Text] [PDF]