Acute systemic inflammation up-regulates secretory sphingomyelinase in vivo: a possible link between inflammatory cytokines and atherogenesis.
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.
Wong
M L
ML
Department of Psychiatry and Biobehavioral Sciences, University of California, School of Medicine, Los Angeles, CA 90095-1761, USA.
Xie
B
B
Beatini
N
N
Phu
P
P
Marathe
S
S
Johns
A
A
Gold
P W
PW
Hirsch
E
E
Williams
K J
KJ
Licinio
J
J
Tabas
I
I
D000208:Acute Disease; D000818:Animals; D001161:Arteriosclerosis / Q000276:immunology*; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D005260:Female; D006801:Humans; D007249:Inflammation; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000008:administration & dosage / Q000276:immunology*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012795:Sialoglycoproteins / Q000235:genetics / Q000276:immunology*; D013108:Sphingomyelin Phosphodiesterase / Q000097:blood*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology*
D016207:Cytokines; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D013108:Sphingomyelin Phosphodiesterase; D020170:Caspase 1