HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Markiewski, M. M. Articles by Lambris, J. D. Search for Related Content PubMed PubMed Citation Articles by Markiewski, M. M. Articles by Lambris, J. D.

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. Lambris^4,*

^* Department of Pathology and Laboratory Medicine, Medical School of the University of Pennsylvania, Philadelphia, PA 19104; Pulmonary Division, Children’s Hospital, 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

Complement effectors are known to contribute to host cell injury in several inflammatory diseases. Contrary to this paradigm, 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 pathways. 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 costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI068730 (to J.D.L.) and AI025011 and AI074333 (to R.A.W.).

² M.M.M. and R.A.D. contributed equally to this work.

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 Pathology and Laboratory Medicine, Medical School of the University of Pennsylvania, 422 Curie Boulevard, Stellar-Chance Building, Room 401C, Philadelphia, PA 19104. E-mail: lambris{at}upenn.edu

⁵ Abbreviations used in this paper: PHx, partial hepatectomy; mTOR, mammalian target of rapamycin; C3aR, C3a receptor; C5aR, C5a receptor.