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ING4 alleviated lipopolysaccharide-induced inflammation by regulating the NF-κB pathway via a direct interaction with SIRT1.
- Source :
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Immunology and cell biology [Immunol Cell Biol] 2020 Feb; Vol. 98 (2), pp. 127-137. Date of Electronic Publication: 2020 Jan 14. - Publication Year :
- 2020
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Abstract
- Sepsis is a complex inflammatory disorder in which high mortality is associated with an excessive inflammatory response. Inhibitor of growth 4 (ING4), which is a cofactor of histone acetyltransferase and histone deacetylase complexes, could negatively regulate this inflammation. However, the exact molecular signaling pathway regulated by ING4 remains uncertain. As a pivotal histone deacetylase, Sirtuin1 (SIRT1), which is widely accepted to be an anti-inflammatory molecule, has not been found to be linked to ING4. This study investigated how ING4 is involved in the regulation of inflammation by constructing lipopolysaccharide (LPS)-induced macrophage and mouse sepsis models. Our results revealed that ING4 expression decreased, whereas the levels of proinflammatory cytokines increased in LPS-stimulated cultured primary macrophages and RAW 264.7 cells. ING4 transfection was confirmed to alleviate the LPS-induced upregulation of proinflammatory cytokine expression both in vitro and in vivo. In addition, ING4-overexpressing mice were hyposensitive to an LPS challenge and displayed reduced organ injury. Furthermore, immunoprecipitation indicated a direct interaction between ING4 and the SIRT1 protein. Moreover, ING4 could block nuclear factor-kappa B (NF-κB) P65 nuclear translocation and restrict P65 acetylation at lysine 310 induced by LPS treatment. These results are the first to clarify that the anti-inflammatory role of ING4 is associated with SIRT1, through which ING4 inhibits NF-κB signaling activation. Our studies provide a novel signaling axis involving ING4/SIRT1/NF-κB in LPS-induced sepsis.<br /> (© 2020 The Authors. Immunology & Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)
- Subjects :
- Acetylation
Animals
Carrier Proteins genetics
Inflammation chemically induced
Inflammation genetics
Lipopolysaccharides
Macrophages drug effects
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Microfilament Proteins metabolism
Protein Binding
RAW 264.7 Cells
Sepsis genetics
Sepsis pathology
Signal Transduction genetics
Sirtuin 1 genetics
Tumor Suppressor Proteins genetics
Up-Regulation
Carrier Proteins metabolism
Inflammation metabolism
Macrophages metabolism
NF-kappa B metabolism
Sepsis metabolism
Sirtuin 1 metabolism
Tumor Suppressor Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1440-1711
- Volume :
- 98
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Immunology and cell biology
- Publication Type :
- Academic Journal
- Accession number :
- 31811786
- Full Text :
- https://doi.org/10.1111/imcb.12308