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Peritonitis, and Cytokine Production in Vivo Anaphylatoxin-Induced Neutropenia, a Critical Role for Sphingosine Kinase In

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Peritonitis, and Cytokine Production in Vivo Anaphylatoxin-Induced Neutropenia, a Critical Role for Sphingosine Kinase In A Critical Role for Sphingosine Kinase in Anaphylatoxin-Induced Neutropenia, Peritonitis, and Cytokine Production in Vivo This information is current as Liudmila Pietrovna Vlasenko and Alirio J. Melendez of September 23, 2021. J Immunol 2005; 174:6456-6461; ; doi: 10.4049/jimmunol.174.10.6456 http://www.jimmunol.org/content/174/10/6456 Downloaded from References This article cites 40 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/174/10/6456.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 23, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology A Critical Role for Sphingosine Kinase in Anaphylatoxin-Induced Neutropenia, Peritonitis, and Cytokine Production in Vivo1 Liudmila Pietrovna Vlasenko and Alirio J. Melendez2 The aim of our study was to investigate the roles played by sphingosine kinase (SPHK) in the anaphylatoxin C5a-triggered responses in vivo. Our data show that i.v. administration of C5a triggers a rapid neutropenic response, but pretreating mice with the SPHK inhibitor, N,N-dimethylsphingosine (DMS), 10 min before the C5a i.v. administration substantially inhibited the C5a- triggered neutropenia. Similarly the i.v. administration of C5a caused a rapid increase in the serum levels of TNF-␣ and IL-6, and this increase in cytokine levels was blocked by DMS. We then induced acute peritonitis with C5a. The C5a i.p. injection triggered a fast recruitment of neutrophils, later followed by monocytes, into the peritoneal cavity. Vascular permeability was also observed: Downloaded from when we i.v. injected Evans blue before C5a i.p. injection, we could observe a continued influx of the dye into the peritoneum. In mice pretreated with DMS, there was a significant reduction on the C5a-triggered neutrophil and monocyte infiltration, as well as a marked reduction on the Evans blue influx. Our data also show that the i.p. administration of C5a caused a rapid increase in TNF-␣ and IL-6 levels in the peritoneal cavity, and this increase in cytokine levels was substantially inhibited in mice pretreated with the SPHK inhibitor. Taken together, these observations suggest a potential role for SPHK in the C5a-triggered inflammatory responses in vivo. The Journal of Immunology, 2005, 174: 6456–6461. http://www.jimmunol.org/ ctivation of the complement cascade plays a key role in ated with the use of such proteins to treat human patients. Immu- host defense. However, activation of the complement nogenicity is a problem, and proteins are expensive to A system leads to the generation of the potent proinflam- manufacture, very susceptible to degradation by proteases in serum matory anaphylatoxin, C5a. Significant amounts of C5a, as well as or the gastrointestinal track, and generally display poor pharma- other complement products in the blood, can lead to a series of ad- cokinetic properties. More recently attempts have been made to verse effects associated with a variety of pathologies, including septic make smaller molecules that are more stable, cheaper to make, shock, adult respiratory distress syndrome, and immune complex-de- have better bioavailability, and are more attractive as drug candi- pendent autoimmune diseases such as rheumatoid arthritis (1–3). dates for treating human diseases mediated by C5a (15, 16). How- by guest on September 23, 2021 Recently, the anaphylatoxin C5a has been shown to have an ever, very little is known about the intracellular signaling pathways immune-regulatory role able to stimulate mediators of both acute activated by C5a in immune-effector cells. and chronic inflammation (4–8). The significance of C5a in sev- During the last few years, it has become clear that sphingolipids, eral inflammatory diseases is demonstrated by the fact that agents in addition to being structural constituents of cell membranes, are that blocked the action of C5a also suppressed inflammation in sources of important signaling molecules. Particularly, the sphin- several animal models (9–13). golipid metabolites, ceramide and sphingosine-1-phosphate In primates, Escherichia coli-induced septic shock and adult re- (SPP),3 have emerged as a new class of potent bioactive mole- spiratory distress syndrome can be attenuated by blocking C5a cules, implicated in a variety of cellular processes such as cell with specific Abs (1, 4). Studies in rats showed that LPS-induced differentiation, apoptosis, and proliferation (17–20). Interest in septic shock can be mimicked by injection of C5a, and Ab block- SPP focused recently on two distinct cellular actions of this lipid: ing of C5a substantially reduces the LPS-induced shock (2). More- namely, its function as an extracellular ligand activating specific G over, blockade of C5a after infusion of LPS or induction of cecal protein-coupled receptors, and its role as an intracellular second ligation puncture in rats has been found to be protective (2, 12). messenger (21). Several findings enforced the notion of SPP as an Furthermore, C5a blockade after cecal ligation puncture in rats important intracellular second messenger. First, activation of var- attenuates the development of multiorgan failure (13). ious plasma membrane receptors, such as the platelet-derived Most of these studies used blocking Abs raised against C5a (10, growth factor receptor (22, 23), the Fc⑀RI and Fc␥RI Ag receptors 12) or recombinant proteins that are receptor antagonists or ana- (24–26), as well as the fMLP receptor (27), was found to rapidly logues of C5a (9, 14). However, there are many problems associ- increase intracellular SPP production through the stimulation of sphingosine kinase (SPHK). Second, inhibition of SPHK stimula- tion strongly reduced or even prevented cellular events triggered Department of Physiology, National University of Singapore, Singapore by these receptors, such as receptor-stimulated DNA synthesis, 2ϩ Received for publication November 5, 2004. Accepted for publication March 3, 2005. Ca mobilization and vesicular trafficking (22–27). The costs of publication of this article were defrayed in part by the payment of page Very recently, we have shown that in human neutrophils and charges. This article must therefore be hereby marked advertisement in accordance macrophages, C5a activates the intracellular signaling molecule with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This work was supported by a grant from the NMRC (R-185-000-052-213). 2 Address correspondence and reprint requests to Dr. Alirio J. Melendez, Department of Physiology, 2 Medical Drive, MD9 #01-05, Singapore 117597. E-mail address: 3 Abbreviations used in this paper: SPP, sphingosine-1-phosphate; DMS, N,N-di- [email protected] methylsphingosine; SPHK, sphingosine kinase; PMN, polymorphonuclear neutrophil. Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 The Journal of Immunology 6457 SPHK and that inhibition of SPHK activity, by N,N-dimethyl- differ significantly in replicate experiments, the results were pooled for sphingosine (DMS), in primary human neutrophils, neutrophil-dif- statistical analyses and for presentation. ferentiated HL-60 cells, as well as in monocyte-derived macro- phages, largely inhibits C5a-stimulated Ca2ϩ mobilization, Results enzyme release, chemotaxis, and cytokine production, suggesting C5a-triggered neutropenia a potential role for SPHK in the C5a-triggered inflammatory re- Agents that trigger acute inflammation or endotoxic shock induce sponses (28, 29). neutropenia. Anaphylatoxins, such as C5a, can induce neutropenia Here we show for the first time that the C5a-triggered neutro- in animal models (30). We have recently demonstrated that in hu- penia and peritonitis can be attenuated by inhibition of SPHK. We man neutrophils and macrophages the intracellular signaling mol- show here that the C5a-triggered neutrophil and monocyte infil- ecule SPHK plays a key role in the inflammatory responses trig- tration into the peritoneal cavity is inhibited in mice pretreated gered by C5a (28, 29). Here we show that administration of a bolus with the SPHK inhibitor, as well as the cytokine levels found in i.v. dose of recombinant human C5a in mice resulted in the rapid serum and in the peritoneal lavage. Thus, our data supports a crit- decrease of circulating PMNs, dropping to 20 Ϯ 5%, of the levels ical role for SPHK in anaphylatoxin-induced inflammatory observed in the unstimulated/controls by 5 min after the C5a i.v., responses. then returning to normal/control values by 1 h (Fig. 1A). However, in mice pretreated with DMS 10 min before C5a administration, the PMN levels were similar to that of the unstimulated controls Materials and Methods All materials unless stated otherwise were bought from Sigma-Aldrich. Downloaded from Mice Male BALB/c mice (8–10 wk old) were obtained from the National Uni- versity of Singapore, Sembawang Laboratory Animals Centre. All animal experiments conducted in this study were performed in accordance with Animal Experimentation Ethics Committee ethical guidelines. Neutropenia assay http://www.jimmunol.org/ Mice were anesthetized and a catheter was placed in the femoral vein. Mice were i.v. injected with DMS (150 ␮M in a final volume of 200 ␮l of PBS) or 200 ␮l of PBS control injection 10 min before C5a challenge. Mice were then given a bolus i.v.
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