NF-κB RelA Is Required for Hepatoprotection during Pneumonia and Sepsis
| Autor: | Matthew R. Jones, Y. Kim, Lee J. Quinton, Elise M. Symer, Eri Allen, Joseph P. Mizgerd, Katrina E. Traber, L. Baird, C. Odom, Filiz T. Korkmaz, E. Na |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
STAT3 Transcription Factor Kupffer Cells Immunology Inflammation Apoptosis Biology medicine.disease_cause Microbiology Sepsis 03 medical and health sciences Mice 0302 clinical medicine Streptococcus pneumoniae medicine Animals Acute-Phase Reaction Chemokine CCL2 Liver injury Host Response and Inflammation Tumor Necrosis Factor-alpha Acute-phase protein Transcription Factor RelA Pneumonia medicine.disease Mice Inbred C57BL 030104 developmental biology Infectious Diseases Hepatoprotection Liver 030220 oncology & carcinogenesis Natural Killer T-Cells Parasitology Tumor necrosis factor alpha medicine.symptom |
| Zdroj: | Infection and immunity. 87(8) |
| ISSN: | 1098-5522 |
| Popis: | Pneumonia and sepsis are distinct but integrally linked public health concerns. The hepatic acute-phase response (APR), which is largely dependent on transcription factors NF-κB RelA and STAT3, is a hallmark of these pathologies and other injurious conditions. Inactivation of the APR can promote liver injury, a frequently observed organ dysfunction during sepsis. However, whether or how the acute-phase changes promote liver tissue resilience during infections is unclear. To determine the hepatoprotective role of the hepatic APR, we utilized mice bearing hepatocyte-specific deletions of either RelA or STAT3. Mice were challenged intratracheally (i.t.), intravenously (i.v.), or intraperitoneally (i.p.) with Escherichia coli, Klebsiella pneumoniae, Streptococcus pneumoniae, lipopolysaccharide (LPS), or alpha-galactosylceramide (αGalCer) to induce pneumonia, sepsis, or NKT cell activation. Liver injury was observed in RelA-null (hepRelA(Δ/Δ)) mice but not STAT3-null (hepSTAT3(Δ/Δ)) mice during pneumonia. The absence of RelA resulted in hepatotoxicity across several models of pneumonia, sepsis, and NKT cell activation. Injury was associated with increased levels of activated caspase-3 and -8 and substantial alteration of the hepatic transcriptome. Hepatotoxicity in the absence of RelA could be reversed by neutralization of tumor necrosis factor alpha (TNF-α). These results indicate the requirement of RelA-dependent inducible hepatoprotection during pneumonia and sepsis. Further, the results demonstrate that RelA-dependent gene programs are critical for maintaining liver homeostasis against TNF-α-driven immunotoxicity. |
| Databáze: | OpenAIRE |
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