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.