Acute systemic inflammation up-regulates secretory sphingomyelinase in vivo: a possible link between inflammatory cytokines and atherogenesis.

Abstract

Inflammation plays a critical role in atherogenesis, yet the mediators linking inflammation to specific atherogenic processes remain to be elucidated. One such mediator may be secretory sphingomyelinase (S-SMase), a product of the acid sphingomyelinase gene. The secretion of S-SMase by cultured endothelial cells is induced by inflammatory cytokines, and in vivo data have implicated S-SMase in subendothelial lipoprotein aggregation, macrophage foam cell formation, and possibly other atherogenic processes. Thus, the goal of this study was to seek evidence for S-SMase regulation in vivo during a physiologically relevant inflammatory response. First, wild-type mice were injected with saline or lipopolysaccharide (LPS) as a model of acute systemic inflammation. Serum S-SMase activity 3 h postinjection was increased 2- to 2.5-fold by LPS (P < 0.01). To determine the role of IL-1 in the LPS response, we used IL-1 converting enzyme knockout mice, which exhibit deficient IL-1 bioactivity. The level of serum S-SMase activity in LPS-injected IL-1 converting enzyme knockout mice was approximately 35% less than that in identically treated wild-type mice (P < 0.01). In LPS-injected IL-1-receptor antagonist knockout mice, which have an enhanced response to IL-1, serum S-SMase activity was increased 1. 8-fold compared with LPS-injected wild-type mice (P < 0.01). Finally, when wild-type mice were injected directly with IL-1beta, tumor necrosis factor alpha, or both, serum S-SMase activity increased 1. 6-, 2.3-, and 2.9-fold, respectively (P < 0.01). These data show regulation of S-SMase activity in vivo and they raise the possibility that local stimulation of S-SMase may contribute to the effects of inflammatory cytokines in atherosclerosis.

• Authors: M L Wong, B Xie, N Beatini, P Phu, S Marathe, A Johns, P W Gold, E Hirsch, K J Williams, J Licinio, I Tabas
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 97 Issue 15 Pg. 8681-6 (Jul 18 2000) ISSN: 0027-8424 [Print] United States
• PMID: 10890909 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cytokines
• IL1RN protein, human
• Il1rn protein, mouse
• Interleukin 1 Receptor Antagonist Protein
• Interleukin-1
• Lipopolysaccharides
• Sialoglycoproteins
• Tumor Necrosis Factor-alpha
• Sphingomyelin Phosphodiesterase
• Caspase 1

Topics

• Acute Disease
• Animals
• Arteriosclerosis (immunology)
• Caspase 1 (genetics, immunology)
• Cytokines (immunology)
• Female
• Humans
• Inflammation
• Interleukin 1 Receptor Antagonist Protein
• Interleukin-1 (administration & dosage, immunology)
• Lipopolysaccharides (administration & dosage, immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Sialoglycoproteins (genetics, immunology)
• Sphingomyelin Phosphodiesterase (blood)
• Tumor Necrosis Factor-alpha (administration & dosage, immunology)
• Up-Regulation (immunology)