In vivo inhibition of Fas ligand-mediated killing by TR6, a Fas ligand decoy receptor.
TR6, a member of the tumor necrosis factor (TNF) receptor superfamily, has recently been shown to bind to Fas ligand (FasL) and inhibit FasL-mediated cell killing in vitro. In the current study, we demonstrate that TR6 can block the lethal activity of FasL in multiple in vitro systems, and extend this finding to an in vivo model of hepatitis. The binding of human TR6 to human FasL was verified with BIAcore chip technology. Human primary hepatocytes, HT-29 cells and Jurkat cells were assayed for viability to demonstrate TR6 inhibition of FasL-mediated cytotoxicity in vitro. Human TR6 was also shown to cross-react with membrane-bound mouse FasL, since the in vitro cytotoxic activity of L929 cells transfected with murine FasL was inhibited in the presence of human TR6. In vivo, FasL-induced acute, lethal, fulminant hepatic apoptosis resulting in death within 2 h of intravenous injection into Fas+ mice, but not Fas- MRL/lpr mice. Pretreatment of mice with TR6 blocked FasL-induced mortality, presumably by attenuating FasL-induced hepatic apoptosis. Thus, in both in vitro and in vivo systems, TR6 acts as a functional FasL decoy receptor and may be clinically useful in the treatment of hepatitis and other diseases associated with FasL-mediated tissue injury.
Connolly
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K
Human Genome Sciences Inc., Rockville, Maryland 20850, USA. kevin_connolly@hgsi.com
Cho
Y H
YH
Duan
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Fikes
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Gregorio
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LaFleur
D W
DW
Okoye
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Salcedo
T W
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Santiago
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Ullrich
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Wei
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Windle
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Wong
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Yao
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Zhang
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Zheng
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Moore
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D053222:Fas Ligand Protein; D005260:Female; D019073:HT29 Cells / Q000187:drug effects / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D019169:Jurkat Cells / Q000187:drug effects / Q000502:physiology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides; D010455:Peptides / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor; D053323:Receptors, Tumor Necrosis Factor, Member 6b
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D009842:Oligopeptides; D010455:Peptides; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D053323:Receptors, Tumor Necrosis Factor, Member 6b; C505911:TNFRSF6B protein, human; C085706:FLAG peptide