| Hepatocyte-specific mutation of both NF-κB RelA and STAT3 abrogates the acute phase response in mice. | |
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MedLine Citation:
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PMID: 22466650 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-04-02 |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 122 ISSN: 1558-8238 ISO Abbreviation: J. Clin. Invest. Publication Date: 2012 May |
Date Detail:
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Created Date: 2012-05-01 Completed Date: 2012-06-29 Revised Date: 2013-05-20 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 1758-63 Citation Subset: AIM; IM |
Affiliation:
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The Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA. lquinton@bu.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acute-Phase Reaction
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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:
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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 HL104053-03/HL/NHLBI NIH HHS; R01-HL068153/HL/NHLBI NIH HHS; R01-HL079392/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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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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