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Programmed Necrotic Cell Death Induced by Complement Involves a Bid-Dependent Pathway¹

Lea Ziporen^*, Natalie Donin^*, Taisia Shmushkovich^*, Atan Gross and Zvi Fishelson^2,*

^* Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; and Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel

The membrane attack complex (MAC) of the complement system induces a necrotic-type cell death. Earlier findings suggested that Bcl-2 protects cells from MAC-induced necrosis. Here we examined the involvement of Bid, a proapoptotic protein, in MAC-induced cytotoxicity. Bid knockout (Bid–/–) mouse embryonic fibroblasts (MEF) and primary fibroblasts were damaged by complement but to a significantly lower extent than wild-type (WT) fibroblasts. Bid silencing with small interfering RNA duplexes led to elevated resistance of mouse fibroblasts, human K562, and Jurkat cells to lysis by complement. Bid–/– MEF were also resistant to toxic doses of streptolysin O, melittin, and A23187. Analysis of complement protein deposition on fibroblasts demonstrated that less complement C3 and C9 bound to Bid–/– than to WT cells, even though expression of the membrane complement inhibitors Crry and CD59 was relatively reduced on Bid–/– cells. Bid was rapidly cleaved in WT MEF subjected to lytic doses of MAC. Pretreatment of the cells with the pan-caspase inhibitor z-Val-Ala-Asp(OMe)-fluoromethylketone reduced Bid cleavage and cell lysis. These results indicate that complement MAC activates two cell death pathways, one involving caspases and Bid and one that is Bid-independent.

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 research was in part supported by grants from the Israel Science Foundation, the Israel Cancer Association, and the Israel Cancer Research Foundation.

² Address correspondence and reprint request to Dr. Zvi Fishelson, Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. E-mail address: lifish{at}post.tau.ac.il

³ Abbreviations used in this paper: MAC, complement membrane attack complex; C8D, C8-deficient human serum; HIS, heat-inactivated serum; KO, knockout; MBL, mannose-binding lectin; MEF, mouse embryonic fibroblasts; MFI, mean fluorescence intensity; NHS, normal human serum; PI, propidium iodide; siRNA, small interfering RNA; SLO, streptolysin O; zVAD, z-Val-Ala-Asp(OMe)-fluoromethylketone; WT, wild type.