Sphingosine kinase-1 mediates endotoxemia-induced hyperinflammation in aged animals

Abstract

Sepsis is a serious issue in the geriatric population due to its association with high mortality rates in the elderly. The increase in mortality in the elderly correlates with inflammation. We have previously demonstrated that the inflammatory response is exacerbated in a rodent endotoxemia model of sepsis in aged rats compared with young rats. However, the molecular mediators associated with this hyperinflammatory response in aged rats have not been completely determined. Sphingosine kinase-1 (Sphk-1), an enzyme present in neutrophils and macrophages, regulates proinflammatory responses associated with endotoxemia and sepsis. To determine whether Sphk-1 is a molecular mediator associated with the observed hyperinflammatory response in aging, Sphk-1 mRNA expression was examined in hepatic tissues of young and aged rats subjected to endotoxemia. A significant increase in Sphk-1 mRNA was observed in endotoxemic aged rats compared with young rats. This increase was correlated with a significant increase in TNF-α mRNA levels in the liver. CD14 is a receptor component for lipopolysaccharide (LPS) and therefore, CD14 mRNA expression in hepatic tissues of endotoxemic young and aged rats was examined. Of note, CD14 mRNA was significantly upregulated in endotoxemic aged rats. Sphk-1 mRNA expression was significantly elevated in LPS-treated Kupffer cells and this increase correlated with an increase in CD14 mRNA expression. Results of the present study indicated that increased Sphk-1 expression in the liver in response to endotoxemia mediates the hyperinflammatory state observed in aged animals.