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The Regulation of Liver Cell Survival by Complement Maciej M The Regulation of Liver Cell Survival by Complement Maciej M. Markiewski, Robert A. DeAngelis, Christoph W. Strey, Periklis G. Foukas, Craig Gerard, Norma Gerard, Rick This information is current as A. Wetsel and John D. Lambris of September 27, 2021. J Immunol 2009; 182:5412-5418; ; doi: 10.4049/jimmunol.0804179 http://www.jimmunol.org/content/182/9/5412 Downloaded from References This article cites 33 articles, 5 of which you can access for free at: http://www.jimmunol.org/content/182/9/5412.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • 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 by guest on September 27, 2021 *average 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 © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology The Regulation of Liver Cell Survival by Complement1 Maciej M. Markiewski,2* Robert A. DeAngelis,2* Christoph W. Strey,3* Periklis G. Foukas,* Craig Gerard,† Norma Gerard,† Rick A. Wetsel,‡ and John D. Lambris4* Complement effectors are known to contribute to host cell injury in several inflammatory diseases. Contrary to this para- digm, in this study utilizing surgical liver resection (partial hepatectomy) in various complement-deficient mice as a model, we have demonstrated that complement anaphylatoxins C3a and C5a are required for the survival of liver cells during regeneration. The mechanisms of these cytoprotective functions of complement were related to the regulation of IL-6 and TNF production or release after liver resection. Disturbances in the cytokine milieu, induced by a loss of complement activity, were found to alter prosurvival signaling, including the IL-6/STAT3 and PI3K/Akt/mammalian target of rapamycin path- ways. In conclusion, this study documents functions of complement proteins as prosurvival factors that, through their interactions with cytokines, inhibit apoptotic signaling in proliferating cells of epithelial origin. The Journal of Immunology, 2009, 182: 5412–5418. Downloaded from he complement system, which is an important contributor injury after partial hepatectomy (PHx)5 (11). The presence of such to innate and adaptive immune responses, is composed severe damage to liver parenchyma in mice lacking complement T of cell membrane regulators and receptors and several components unexpectedly points to the importance of these pro- circulating plasma proteins, forming a proteolytic cascade that teins for prosurvival signaling triggered during liver regeneration. is immediately activated when rapid initiation of the inflamma- Liver regeneration is a compensatory hyperplasia occurring as a http://www.jimmunol.org/ tory reaction is needed (1). Activation of complement leads to response to the loss of liver mass caused by injury or surgical the generation of several complement effectors, including the resection, and it is regulated by the interplay between cytokines anaphylatoxins C3a and C5a. Anaphylatoxins can enhance in- and growth factors (13). Dividing and enlarging liver cells require flammation, either by directly binding to their receptors on tar- factors that regulate cell growth and proliferation. Additionally, get cells or by acting indirectly through interactions with other several mechanisms that inhibit death signaling are activated in contributors to the inflammatory response (1). Although the these cells. Recent investigations have shown that some of the function of inflammation is to eliminate pathogens, under cer- factors implicated in the regulation of liver cell proliferation are tain clinical conditions it may cause more damage than the also important for the survival of regenerating liver cells (13, 14). pathogens themselves (2). Inflammation-mediated tissue dam- Antiapoptotic signaling triggered by these factors includes the by guest on September 27, 2021 age is a major pathogenetic mechanism in several inflammatory PI3K/Akt/mammalian target of rapamycin (mTOR) pathway. The disorders, including systemic lupus erythematosus (3, 4) and PI3K, Akt, and mTOR proteins comprise one of the best charac- ischemia/reperfusion-induced tissue injury (5–7). In these dis- terized prosurvival signaling pathways and are also involved in the eases complement enhances tissue injury through its contribu- regulation of several other crucial cellular processes, including tion to inflammation (8, 9). transcription, translation, metabolism, and cell cycle progression Previous work has shown the involvement of the complement (15). It has been also suggested that IL-6, produced and secreted proteins C3a and C5a in the priming phase of liver regeneration by activated Kupffer cells, is a major activator of this prosurvival (10–12). A lack of complement signaling in complement-deficient signaling in regenerating liver cells (16). mice resulted in impaired liver regeneration. Intriguingly, various We now present evidence that complement anaphylatoxins gen- complement deficiencies were also associated with significant liver erated through activation of the complement cascade contribute to the activation of this signaling by regulating the cytokine milieu during liver regeneration, and that this contribution is essential for *Department of Pathology and Laboratory Medicine, Medical School of the Univer- sity of Pennsylvania, Philadelphia, PA 19104; †Pulmonary Division, Children’s Hos- the survival of liver cells during regeneration. pital, Boston, MA 02215; and ‡Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, TX 77030 Materials and Methods Animal studies Received for publication December 16, 2008. Accepted for publication February 16, 2009. Complement-deficient mice lacking C3 (C3Ϫ/Ϫ), the C3a receptor (C3aRϪ/Ϫ), Ϫ Ϫ Ϫ Ϫ The costs of publication of this article were defrayed in part by the payment of page the C5a receptor (C5aR / ), or both C3 and C5 (C3/C5 / ) have been charges. This article must therefore be hereby marked advertisement in accordance previously described (11, 17–19). Complement-deficient mice were back- with 18 U.S.C. Section 1734 solely to indicate this fact. crossed for at least nine generations onto a C57BL/6 background, and their 1 This work was supported by National Institutes of Health Grants AI068730 (to wild-type littermates or C57BL/6J mice (The Jackson Laboratory) were J.D.L.) and AI025011 and AI074333 (to R.A.W.). used as controls. For PHx studies, male mice 12–16 wk of age were anesthetized and 2 M.M.M. and R.A.D. contributed equally to this work. subjected to midventral laparotomy with ϳ70% liver resection (PHx) (20). 3 Current address: Department of General and Vascular Surgery, Johann Wolfgang Goethe University, Frankfurt, Germany. 4 Address correspondence and reprint requests to Dr. John D. Lambris, Department of 5 Abbreviations used in this paper: PHx, partial hepatectomy; mTOR, mammalian Pathology and Laboratory Medicine, Medical School of the University of Pennsyl- target of rapamycin; C3aR, C3a receptor; C5aR, C5a receptor. vania, 422 Curie Boulevard, Stellar-Chance Building, Room 401C, Philadelphia, PA 19104. E-mail: [email protected] Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.0804179 The Journal of Immunology 5413 Control animals were subjected to midventral laparotomy without manip- ulation of the liver (sham). Histological slides from the resected liver lobes were analyzed to exclude preexisting pathology. One hour before sacrifice, at0horafter 12 h, BrdU (Sigma-Aldrich) was injected i.p. at a single dose of 50 mg/kg animal weight. At the time of sacrifice, clinical status was assessed, mice were anesthetized, blood was harvested from the inferior vena cava, and the remaining liver lobes and other internal organs were removed, weighed, and processed for protein or histological analysis. Histological slides prepared from lungs, kidneys, spleen, intestine, and pancreas of sacrificed mice were analyzed for the presence of any mor- phological abnormalities that could indicate infection. Mice with an inflammatory infiltrate in any of the internal organs were excluded from further analysis. To assess complement activation or the levels of cy- tokines secreted during liver regeneration, 30 ␮l of blood was collected with EDTA (for plasma) or without anticoagulant (for serum) from the tail vein before and 0.5, 1, 2, 3, 6, 12, 24, 48, and 72 h after PHx. Plasma and serum were separated by gentle centrifugation (1000 ϫ g) at 4°C for 10 min and then stored at Ϫ70°C until analyzed. For reconstitution studies, C3/C5Ϫ/Ϫ mice were injected i.p. with three successive doses of synthetic mouse C3a and/or C5a 20 min before and at two 6-h intervals after PHx (15 ␮g/mouse/injection). Synthesis of mouse C3a and expression of C5a has been described previously (11). C3Ϫ/Ϫ mice were reconstituted
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