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 link ing inflammation to specific atherogenic processes remain to be elucidated. One such mediator may be secretory sphingomyelinase (S-SMase), a product o f the acid sphingomyelinase gene. The secretion of S-SMase by cultured endo thelial cells is induced by inflammatory cytokines, and in vivo data have i mplicated S-SMase in subendothelial lipoprotein aggregation, macrophage foa m 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 system ic 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 res ponse, we used IL-1 converting enzyme knockout mice, which exhibit deficien t IL-1 bioactivity. The level of serum S-SMase activity in LPS-injected IL- 1 converting enzyme knockout mice was approximate to 35% less than that in identically treated wild-type mice (P < 0.01). In LPS-injected IL-1-recepto r 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-typ e mice (P < 0.01). Finally, when wild-type mice were injected directly with IL-1 beta, tumor necrosis factor or, or both, serum S-SMase activity incre ased 1.6-, 2.3-, and 2.9-fold, respectively (P < 0.01). These data show reg ulation of S-SMase activity in vivo and they wise the possibility that loca l stimulation of S-SMase may contribute to the effects of inflammatory cyto kines in atherosclerosis.