Effects of ceramide kinase knockout on lipopolysaccharide-treated sepsis-model mice: Changes in serum cytokine/chemokine levels and increased lethality

Abstract

Ceramide, a central molecule of sphingolipid metabolism, is phosphorylated to ceramide-1-phosphate (C1P) by ceramide kinase (CerK). The CerK/C1P pathway regulates many cellular functions, but its roles in immune/inflammation-related (IIR) diseases in vivo are not well known. Sepsis is an acute systemic inflammatory disease accompanied by damage/dysfunction in multiple organs. In the present study, we investigated the effects of CerK knockout on the onset/progression of sepsis-related events in lipopolysaccharide (LPS)-treated sepsis-model mice. In CerK-null mice, the lethality at 48 h after i.v. injection of LPS was significantly increased compared with that in wild-type (WT) mice. The increased lethality by CerK knockout was reproduced in mice treated with i.p. injections of LPS. Changes in serum levels of 23 IIR molecules, including cytokines and chemokines, were measured. In WT mice, levels of these molecules increased 4 and/or 20 h after i.v. injection of LPS. Although the basal levels of IIR molecules were not affected, LPS-induced increases in interleukin-17 (IL-17), C-C motif chemokine ligands (CCL-2 and CCL-11), and tumor necrosis factor-α were significantly up-regulated, whereas IL-2 levels were slightly down-regulated by CerK knockout. Putative mechanisms for the CerK/C1P pathway-mediated regulation of IIR molecules and increased lethality in LPS-treated mice are discussed.

Keywords

• Ceramide-1-phosphate
• Neutrophils
• Interleukin-17
• Tumor necrosis factor-α
• Monocyte chemotactic protein-1 (MCP-1)