SphK1 Regulates Proinflammatory Responses Associated with Endotoxin and Polymicrobial Sepsis

Abstract

Sepsis Protection Sepsis is a serious medical condition characterized by an uncontrolled inflammatory response to infection. Sepsis often results in organ failure and/or death, and current treatments are not very effective. Puneet et al. (p. 1290 ) now show that the enzyme sphingosine kinase 1 (SphK1) may represent an important therapeutic target for the treatment of sepsis. SphK1 expression increased on human phagocytes in response to bacterial products and was also highly expressed on phagocytes from septic patients. Inhibition of SphK1 reduced the production of inflammatory mediators in vitro by human phagocytes stimulated with bacterial products. In vivo, pretreatment with small interfering RNA against SphK1 or a specific SphK1 inhibitor protected mice from death in two lethal models of sepsis. Protection was also seen when mice were treated with the SphK1 inhibitor up to 8 hours after sepsis induction, and this protection was enhanced if mice were given a broad-spectrum antibiotic.