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J. Biol. Chem., Vol. 281, Issue 8, 4663-4670, February 24, 2006

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Apoptotic Cells, at All Stages of the Death Process, Trigger Characteristic Signaling Events That Are Divergent from and Dominant over Those Triggered by Necrotic Cells

IMPLICATIONS FOR THE DELAYED CLEARANCE MODEL OF AUTOIMMUNITY^*

Vimal A. Patel, Angelika Longacre, Kevin Hsiao, Hanli Fan, Fanyong Meng, Justin E. Mitchell^¶, Joyce Rauch^||, David S. Ucker^¶, and Jerrold S. Levine^¶1

From the Department of Medicine, Division of Nephrology, University of Illinois at Chicago, Chicago, Illinois 60612, Promega Corporation, Madison, Wisconsin 53711, the ^||Division of Rheumatology, Department of Medicine, Research Institute of the McGill University Health Centre, Montreal, Quebec H3G 1A4, Canada, and the ^¶Department of Immunology and Microbiology, University of Illinois at Chicago, Chicago, Illinois 60612

Current models of autoimmunity suggest that delayed clearance of apoptotic cells leads to the presentation of apoptotic antigens in the context of inflammatory signals, with resultant autoimmunity. These models implicitly assume that, in contrast to early apoptotic cells (that retain membrane integrity), late apoptotic cells (with compromised membranes) act like necrotic cells (which also lack intact membranes), possibly because of the release of proinflammatory intracellular contents. We showed previously that early apoptotic and necrotic cells induce distinct mitogen-activated protein kinase modules in macrophages with which they interact. Exposure to apoptotic cells led to nearly complete inhibition of both basal and macrophage colony-stimulating factor-induced ERK1/2 by macrophages. In contrast, necrotic cells induced ERK1/2. We show here that apoptotic cells also strongly induced both c-Jun N-terminal kinase and p38, whereas necrotic cells had no detectable effect on c-Jun N-terminal kinase and p38. We also compared the signaling events induced in macrophages by exposure to early apoptotic cells, late apoptotic cells, and necrotic cells. The signaling events induced by late apoptotic cells were identical to and just as potent as those induced by early apoptotic cells. Thus, apoptotic cells are functionally equivalent throughout the cell death process, irrespective of membrane integrity. Moreover, the effects of both early and late apoptotic cells on signaling were dominant over those of necrotic cells. These data show that apoptotic cells do not become proinflammatory upon the loss of membrane integrity and are inconsistent with the notion that delayed clearance alone can lead to autoimmunity.

Received for publication, July 29, 2005 , and in revised form, December 21, 2005.

^* This work was supported by National Institutes of Health Grants DK59793 and HL69722 (to J. S. L.) and AG024234 (to D. S. U.), by operating grants from the Arthritis Society of Canada (to J. R.) and the Canadian Institutes of Health Research (to J. R.), and by a Young Investigator Award from the National Kidney Foundation of Illinois (to J. S. L.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S6.

¹ To whom correspondence should be addressed: Dept. of Medicine/Division of Nephrology, MC793, 820 S. Wood St., University of Illinois at Chicago College of Medicine, Chicago, IL 60612. Tel.: 312-413-1178; Fax: 312-996-7378; E-mail: jslevine{at}uic.edu.

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