Fas ligand (FasL) has been shown to mediate both apoptotic and inflammatory reactions. To rigorously assess the physiological role of different forms of the FasL molecule with regard to these two distinct processes, we isolated stably transfected lymphoma cell lines that expressed either murine wild-type FasL, membrane-only FasL, or functionally distinct forms of soluble FasL. First, the ability of these lines to induce an inflammatory response was assessed in vivo by injecting the transfectants intraperitoneally and measuring subsequent neutrophil extravasation into the peritoneal cavity. Second, lines were assessed by injecting the transfectants subcutaneously and monitoring their growth as solid tumors. Our study clearly demonstrated that the extent of inflammation induced by the transfectants directly correlated with their relative cytotoxic activities. A neutrophil response could only be elicited in mice with intact Fas death domains although Fas expression by the neutrophils was not essential. Lymphoma cells expressing the soluble FasL form corresponding to the natural cleavage product could not trigger apoptosis and did not induce a neutrophil response. In contrast to the other FasL transfectants, these cells survived as tumor transplants. However, expression of soluble FasL was not benign, but actually suppressed the inflammatory response and protected other transfectants from the effector mechanisms elicted by membrane-bound FasL.
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3 April 2000
Article|
April 03 2000
Opposing Effects of Transmembrane and Soluble FAS Ligand Expression on Inflammation and Tumor Cell Survival
Andreas M. Hohlbaum,
Andreas M. Hohlbaum
aDepartment of Microbiology, Boston University School of Medicine, Boston, Massachusetts 02118
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Signa Moe,
Signa Moe
aDepartment of Microbiology, Boston University School of Medicine, Boston, Massachusetts 02118
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Ann Marshak-Rothstein
Ann Marshak-Rothstein
aDepartment of Microbiology, Boston University School of Medicine, Boston, Massachusetts 02118
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Andreas M. Hohlbaum
aDepartment of Microbiology, Boston University School of Medicine, Boston, Massachusetts 02118
Signa Moe
aDepartment of Microbiology, Boston University School of Medicine, Boston, Massachusetts 02118
Ann Marshak-Rothstein
aDepartment of Microbiology, Boston University School of Medicine, Boston, Massachusetts 02118
Abbreviations used in this paper: CMFDA, 5-chloromethylfluorescein diacetate; L, ligand; GCSF, granulocyte CSF; HPBS, Hank's PBS; mFasL, membrane-only FasL; PEC, peritoneal exudate cell; PWC, peritoneal washout cell; sFasL, soluble FasL natural cleavage product; sFasL.EX, soluble FasL extracellular domain; wtFasL, wild-type FasL.
Received:
December 08 1999
Revision Requested:
January 21 2000
Accepted:
February 01 2000
Online ISSN: 1540-9538
Print ISSN: 0022-1007
© 2000 The Rockefeller University Press
2000
The Rockefeller University Press
J Exp Med (2000) 191 (7): 1209–1220.
Article history
Received:
December 08 1999
Revision Requested:
January 21 2000
Accepted:
February 01 2000
Citation
Andreas M. Hohlbaum, Signa Moe, Ann Marshak-Rothstein; Opposing Effects of Transmembrane and Soluble FAS Ligand Expression on Inflammation and Tumor Cell Survival. J Exp Med 3 April 2000; 191 (7): 1209–1220. doi: https://doi.org/10.1084/jem.191.7.1209
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