Hepatocyte-specific mutation of both NF-κB RelA and STAT3 abrogates the acute phase response in mice
2012
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- Autor(en) / Beteiligte
- Titel
- Hepatocyte-specific mutation of both NF-κB RelA and STAT3 abrogates the acute phase response in mice
- Ist Teil von
- The Journal of clinical investigation, 2012-05, Vol.122 (5), p.1758-1763
- Ort / Verlag
- United States: American Society for Clinical Investigation
- Erscheinungsjahr
- 2012
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0021-9738eISSN: 1558-8238DOI: 10.1172/JCI59408Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3336975
- Format
- –
- Schlagworte
- Acute-Phase Reaction - blood, Acute-Phase Reaction - genetics, Acute-Phase Reaction - microbiology, Animals, Brief Report, Gene Expression Regulation, Gene Knockout Techniques, Hepatocytes - metabolism, Immunity, Innate, Liver - metabolism, Liver - pathology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Pneumonia, Pneumococcal - blood, Pneumonia, Pneumococcal - genetics, Pneumonia, Pneumococcal - immunology, Serum Amyloid A Protein - metabolism, Serum Amyloid P-Component - metabolism, STAT3 Transcription Factor - genetics, STAT3 Transcription Factor - metabolism, Streptococcus pneumoniae, Transcription Factor RelA - genetics, Transcription Factor RelA - metabolism, Transcriptome