The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/4/1343/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 8, April 19, 1999 1343-1354

Articles

Monocyte-mediated Tumoricidal Activity via the Tumor Necrosis Factor–related Cytokine, TRAIL

Thomas S. Griffith*, Steven R. Wiley{ddagger}, Marek Z. Kubin*, Lisa M. Sedger§, Charles R. Maliszewski§, and Neil A. Fanger§

From the * Department of Immunobiology, the {ddagger} Department of Bioinformatics, and the § Department of Discovery Research, Immunex Corporation, Seattle, Washington 98101

TRAIL (tumor necrosis factor [TNF]-related apoptosis-inducing ligand) is a molecule that displays potent antitumor activity against selected targets. The results presented here demonstrate that human monocytes rapidly express TRAIL, but not Fas ligand or TNF, after activation with interferon (IFN)-{gamma} or -{alpha} and acquire the ability to kill tumor cells. Monocyte-mediated tumor cell apoptosis was TRAIL specific, as it could be inhibited with soluble TRAIL receptor. Moreover, IFN stimulation caused a concomitant loss of TRAIL receptor 2 expression, which coincides with monocyte acquisition of resistance to TRAIL-mediated apoptosis. These results define a novel mechanism of monocyte-induced cell cytotoxicity that requires TRAIL, and suggest that TRAIL is a key effector molecule in antitumor activity in vivo.

Key Words: TRAIL • apoptosis • tumor • monocyte • human

Address correspondence to Neil A. Fanger, Department of Discovery Research, Immunex Corporation, 51 University St., Seattle, WA 98101. E-mail: nfanger{at}immunex.com

Abbreviations used: AICD, activation-induced cell death; L-NMMA, NG-monomethyl-L-arginine; LZ, leucine zipper; M{varphi}, mononuclear phagocyte(s); NO, nitric oxide; RT, reverse transcription; TRAIL, TNF-related apoptosis-inducing ligand.


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