Diacylglycerol kinase ε depletion suppresses LPS-stimulated NF-κB activation and reduces free radical-induced DNA damage.

Abstract

The diacylglycerol kinase (DGK) family regulates lipid-mediated signaling machinery. The present study examined how DGKε depletion affects lipopolysaccharide (LPS)-mediated inflammatory responses at the cellular and organismal levels. In the early phase, DGKε-deficient cells showed reduced phosphorylation levels of Akt and NF-κB p65 subunit. In the animal model of endotoxin shock, DGKε-deficient mice showed full survival (100%) at 24 h after LPS administration, compared to the wild-type mice survival rate of 53%. In this setting, TNF-α and iNOS, the NF-κB-inducible inflammatory genes, were downregulated in DGKε-deficient liver. Furthermore, free radical-mediated cytotoxicity as evaluated by 8-OHdG staining was significantly lower in the liver. Results suggest that DGKε depletion suppresses the NF-κB pathway, thereby conferring resistance to endotoxin shock in mice. Impact statement We examined how DGKε depletion affects LPS-mediated inflammatory responses. At the cellular level, NF-κB signaling was attenuated in DGKε-deficient cells. DGKε-deficient mice were less vulnerable to endotoxin shock than the wild-type. Our results suggest DGKε depletion promotes suppression of the NF-κB pathway, thereby conferring resistance to endotoxin shock in mice.