LPS-mediated septic shock is augmented in ceramide synthase 2 null mice due to elevated activity of TNFα-converting enzyme

• Ceramide synthase 2 (CerS2) null mice are unable to synthesize very-long acyl chain ceramides.
• CerS2 null mice show a number of pathologies in the liver due to alterations of specific biochemical pathways.
• We now show that CerS2 null mice are hypersensitive to LPS-mediated sepsis due to elevated TNFα secretion.
• Elevated TNFα secretion was due to elevated TACE activity in both hepatocytes and macrophages.

Tumor necrosis factor α (TNFα) is an inflammatory cytokine that plays an intimate role in septic shock. Injection of high levels of lipopolysaccharide induces septic shock and death in mice within 30 h, whereas ceramide synthase 2 (CerS2) null mice, defective in the synthesis of very-long acyl chain ceramides, die within ∼10 h. The augmented rate of death of CerS2 null mice is due to elevated levels of TNFα secretion as a result of enhanced activity of TNFα-converting enzyme (TACE). We discuss the relationship between the sphingolipid acyl chain length and TACE activity and the relevance of this data to septic shock.