Document Detail


Hepatocyte-specific mutation of both NF-κB RelA and STAT3 abrogates the acute phase response in mice.
MedLine Citation:
PMID:  22466650     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The acute phase response is an evolutionarily conserved reaction in which physiological stress triggers the liver to remodel the blood proteome. Although thought to be involved in immune defense, the net biological effect of the acute phase response remains unknown. As the acute phase response is stimulated by diverse cytokines that activate either NF-κB or STAT3, we hypothesized that it could be eliminated by hepatocyte-specific interruption of both transcription factors. Here, we report that the elimination in mice of both NF-κB p65 (RelA) and STAT3, but neither alone, abrogated all acute phase responses measured. The failure to respond was consistent across multiple different infectious, inflammatory, and noxious stimuli, including pneumococcal pneumonia. When the effects of infection were analyzed in detail, pneumococcal pneumonia was found to alter the expression of over a thousand transcripts in the liver. This outcome was inhibited by the combined loss of RelA and STAT3. Moreover, this interruption of the acute phase response increased mortality and exacerbated bacterial dissemination during pneumonia, possibly as a result of acute humoral enhancement of macrophage opsonophagocytosis, which was impaired in the mutant mice. Thus, we conclude that RelA and STAT3 are essential for stress-induced transcriptional remodeling in the liver and the subsequent activation of the acute phase response, whose functional role includes compartmentalization of local infection.
Authors:
Lee J Quinton; Matthew T Blahna; Matthew R Jones; Eri Allen; Joseph D Ferrari; Kristie L Hilliard; Xiaoling Zhang; Vishakha Sabharwal; Hana Algül; Shizuo Akira; Roland M Schmid; Stephen I Pelton; Avrum Spira; Joseph P Mizgerd
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-04-02
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  122     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-05-01     Completed Date:  2012-06-29     Revised Date:  2014-09-19    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1758-63     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Acute-Phase Reaction / blood,  genetics,  microbiology*
Animals
Gene Expression Regulation
Gene Knockout Techniques
Hepatocytes / metabolism*
Immunity, Innate
Liver / metabolism,  pathology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Pneumonia, Pneumococcal / blood,  genetics,  immunology*
STAT3 Transcription Factor / genetics*,  metabolism
Serum Amyloid A Protein / metabolism
Serum Amyloid P-Component / metabolism
Streptococcus pneumoniae
Transcription Factor RelA / genetics*,  metabolism
Transcriptome
Grant Support
ID/Acronym/Agency:
1UL1RR025771/RR/NCRR NIH HHS; R00 HL092956/HL/NHLBI NIH HHS; R00-HL092956/HL/NHLBI NIH HHS; R01 HL079392/HL/NHLBI NIH HHS; R01 HL104053/HL/NHLBI NIH HHS; R01-HL068153/HL/NHLBI NIH HHS; R01-HL079392/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Rela protein, mouse; 0/STAT3 Transcription Factor; 0/Serum Amyloid A Protein; 0/Serum Amyloid P-Component; 0/Stat3 protein, mouse; 0/Transcription Factor RelA
Comments/Corrections

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