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Acute Systemic Inflammation Up-Regulates Secretory Sphingomyelinase in Vivo: a Possible Link Between Inflammatory Cytokines and Atherogenesis

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Acute Systemic Inflammation Up-Regulates Secretory Sphingomyelinase in Vivo: a Possible Link Between Inflammatory Cytokines and Atherogenesis Acute systemic inflammation up-regulates secretory sphingomyelinase in vivo: A possible link between inflammatory cytokines and atherogenesis Ma-Li Wong*, Boxun Xie†, Nan Beatini†, Phan Phu‡, Sudhir Marathe†, Anthony Johns§, Philip W. Gold‡, Emmet Hirsch¶, Kevin Jon Williamsʈ, Julio Licinio*, and Ira Tabas†** *Department of Psychiatry and Biobehavioral Sciences, University of California, School of Medicine, Los Angeles, CA 90095-1761; Departments of †Medicine, Anatomy, and Cell Biology and ¶Obstetrics and Gynecology, Columbia University, New York, NY 10032; ‡Clinical Neuroendocrinology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1284; §Berlex Biosciences, Richmond, CA 94804; and ʈDorrance H. Hamilton Research Laboratories, Division of Endocrinology, Diabetes, and Metabolic Diseases, Thomas Jefferson University, Philadelphia, PA 19107 Edited by S. M. McCann, Pennington Biomedical Research Center, Baton Rouge, LA, and approved May 23, 2000 (received for review March 7, 2000) Inflammation plays a critical role in atherogenesis, yet the medi- sphingomyelinase (SMase) (20, 21). Ceramide generated from ators linking inflammation to specific atherogenic processes re- SMase activation has been reported to play roles in cytokine- main to be elucidated. One such mediator may be secretory mediated apoptosis, cellular differentiation, and cellular senes- sphingomyelinase (S-SMase), a product of the acid sphingomyeli- cence (20, 21), each of which may be important in the inflam- nase gene. The secretion of S-SMase by cultured endothelial cells matory response. Whereas studies in vitro have suggested roles is induced by inflammatory cytokines, and in vivo data have for several different mammalian SMase activities in various implicated S-SMase in subendothelial lipoprotein aggregation, ceramide signaling pathways (20, 21), a product of the acid macrophage foam cell formation, and possibly other atherogenic SMase (ASM) gene has been implicated in several specific processes. Thus, the goal of this study was to seek evidence for processes in vivo by molecular genetic studies using the ASM S-SMase regulation in vivo during a physiologically relevant in- knockout mouse (22, 23). In particular, ASM knockout mice are flammatory response. First, wild-type mice were injected with relatively resistance to endothelial apoptosis induced by radia- PHYSIOLOGY saline or lipopolysaccharide (LPS) as a model of acute systemic tion (22) or LPS (23), both of which act through ceramide inflammation. Serum S-SMase activity 3 h postinjection was in- signaling. creased 2- to 2.5-fold by LPS (P < 0.01). To determine the role of IL-1 ASM knockout mice on a hypercholesterolemic genetic back- in the LPS response, we used IL-1 converting enzyme knockout ground also show marked resistance to atherosclerotic lesion mice, which exhibit deficient IL-1 bioactivity. The level of serum development (24). There are two possible scenarios linking ASM S-SMase activity in LPS-injected IL-1 converting enzyme knockout gene products to atherosclerosis. First, inflammation plays an mice was Ϸ35% less than that in identically treated wild-type mice important role in atherogenesis (13–17), and, given the evidence (P < 0.01). In LPS-injected IL-1-receptor antagonist knockout mice, cited above, ASM-mediated ceramide signaling may be respon- which have an enhanced response to IL-1, serum S-SMase activity sible for certain inflammatory responses in the developing was increased 1.8-fold compared with LPS-injected wild-type mice lesion, such as smooth muscle cell proliferation (25) and apo- (P < 0.01). Finally, when wild-type mice were injected directly with ptosis of macrophages and smooth muscle cells (26, 27). Second, IL-1␤, tumor necrosis factor ␣, or both, serum S-SMase activity one of the products of the ASM gene—secretory SMase (S- increased 1.6-, 2.3-, and 2.9-fold, respectively (P < 0.01). These data SMase; see below)—has been linked directly to extracellular show regulation of S-SMase activity in vivo and they raise the subendothelial lipoprotein aggregation, an event that promotes possibility that local stimulation of S-SMase may contribute to the both retention of lipoproteins in the arterial wall and macro- effects of inflammatory cytokines in atherosclerosis. phage foam cell formation (25, 28–39). The ASM gene encodes a single mRNA and protein precursor that gives rise to both S-SMase and lysosomal SMase (L-SMase) he inflammatory response is not only an important compo- via differential trafficking: if the protein precursor is mannose- Tnent in the defense against pathogens, but it is also an phosphorylated, it will be trafficked to lysosomes, whereas if that important contributor to pathophysiologic processes such as same precursor is not mannose-phosphorylated, it is trafficked atherosclerosis, autoimmune diseases, and endotoxic shock (1– to the secretory pathway, generating S-SMase (40). Both L- 10). In atherosclerosis, both clinical and biochemical evidence SMase and S-SMase are absent in ASM knockout mice and in strongly suggest that lesion development, which is initiated by patients with types A and B Niemann–Pick disease (40, 41). lipoprotein retention and aggregation within the vessel wall (11, Although defects in ASM-deficient states often are assumed to 12), can be accelerated by local actions of inflammatory cyto- be caused by an absence of L-SMase (42), it is possible that some kines, notably on endothelial cells (13–17). For example, both of these defects may be the result of the absence of S-SMase, lipopolysaccharide (LPS), the mediator of Gram-negative en- which is the only known extracellular SMase in higher organisms dotoxic shock, and systemic lupus erythematosus have been associated with the development of atherosclerotic lesions (18, 19). This paper was submitted directly (Track II) to the PNAS office. The hallmarks of cytokine biology are pleiotropism and Abbreviations: S-SMase, secretory sphingomyelinase; L-SMase, lysosomal sphingomyeli- redundancy. Although a number of signaling pathways have been nase; ASM, acid sphingomyelinase; LPS, lipopolysaccharide; ICE, IL-1 converting enzyme; ␣ ␣ implicated in mediating the cellular effects of inflammatory IL-1ra, IL-1 receptor antagonist; TNF- , transforming growth factor . cytokines, there is still considerable uncertainty about the **To whom reprint requests should be addressed at: Department of Medicine, Columbia University, 630 West 168th Street, New York, NY 10032. E-mail: [email protected]. relative importance of each of these pathways during inflam- The publication costs of this article were defrayed in part by page charge payment. This matory processes in vivo, including atherosclerosis and endotoxic article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. shock (1, 2). One class of signaling pathways that has received §1734 solely to indicate this fact. considerable attention over the last few years involves the Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073͞pnas.150098097. generation of ceramide by the action of cytokine-stimulated Article and publication date are at www.pnas.org͞cgi͞doi͞10.1073͞pnas.150098097 PNAS ͉ July 18, 2000 ͉ vol. 97 ͉ no. 15 ͉ 8681–8686 Downloaded by guest on September 27, 2021 (43). In this light, subendothelial lipoprotein aggregation is an extracellular event. Similarly, most cellular SM is on the external leaflet of the cellular membrane (44), where it would be inac- cessible to L-SMase. Moreover, any ceramide generated by L-SMase is unable to escape lysosomes (45), raising doubts about its participation as a second messenger. Furthermore, several cell types involved in atherosclerosis and the inflammatory response are rich sources of S-SMase, such as endothelial cells and macrophage (32, 41). Endothelial cells, in particular, have the highest levels of S-SMase secretion of any cultured cell type tested in vitro (32) and the most intense immunostaining of any cell type within vascular tissue samples (34). Finally, several inflammatory cytokines, such as IL-1␤, tumor necrosis factor ␣ (TNF-␣), and IFN-␥ (46), increase the already high levels of S-SMase secretion from cultured endothelial cells and, impor- tantly, decrease the levels of L-SMase in these cells (32). Thus, we propose that S-SMase is a key mediator linking the inflammatory response to atherogenesis and possibly other cytokine-mediated events. An essential test of this hypothesis would be to examine the regulation of S-SMase by cytokines in vivo during a physiologically relevant inflammatory response. The goal of this study, therefore, was to determine whether S-SMase activity is regulated in vivo during the course of acute systemic inflammation. Our data show that S-SMase activity in the serum of mice is, indeed, increased by injection of LPS or by the inflammatory cytokines IL-1␤ and TNF-␣. Furthermore, using two induced mutant mouse models, we show that the effect of LPS injection on serum S-SMase levels is mediated in part by Fig. 1. Serum Zn2ϩ-dependent SMase activity is increased by LPS injection. the endogenous production of IL-1. These findings, which Wild-type mice were injected i.p. with 50 mg͞kg LPS or saline as control, and provide evidence for the regulation of S-SMase in vivo, raise the 3 h later serum was assayed for SMase activity in the presence of EDTA ϩ possibility that local stimulation of S-SMase may play a role in (hatched bars) or Zn2 (solid bars). There were three mice in each group. Each the action of inflammatory cytokines in atherosclerosis. of the four possible pairwise comparisons between groups in this figure (EDTA vs. Zn2ϩ in the saline and LPS groups and saline vs. LPS in the EDTA and Zn2ϩ Experimental Procedures groups) indicated a significant difference (P Ͻ 0.01). Animals. Pathogen-free 20- to 35-g female mice housed in a light-controlled (12-h on͞12-h off) and temperature-controlled administered i.p. by single injection at a dose of 50 mg͞kg. environment with food and water ad libitum were used. Wild- ͞ Groups of IL-1ra knockout and IL-1ra wild-type were given 25 type C57BL 6J mice were obtained from The Jackson Labora- ͞ tory.
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