Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Is an Inhibitor of Autoimmune Inflammation and Cell Cycle Progression

doi:10.1084/jem.191.7.1095

Published online 27 March 2000.

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© The Rockefeller University Press, 0022-1007/2000/4/1095/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 7, April 3, 2000 1095-1104

Original Article

Tumor Necrosis Factor–related Apoptosis-inducing Ligand (TRAIL) Is an Inhibitor of Autoimmune Inflammation and Cell Cycle Progression

Kaimei Song^a, Yiguang Chen^a, Rüdiger Göke^a, Andreas Wilmen^a, Cheryl Seidel^a, Alexandra Göke^a, Brendan Hilliard^a, and Youhai Chen^a
^a Department of Molecular and Cellular Engineering, Institute for Human Gene Therapy, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Correspondence to: Youhai Chen, BRB-II/III, Rm. 511, Institute for Human Gene Therapy and Department of Molecular and Cellular Engineering, University of Pennsylvania School of Medicine, 421 Curie Blvd., Philadelphia, PA 19104. Tel:215-898-4671 Fax:215-573-2275 E-mail:yhc{at}mail.med.upenn.edu.

The tumor necrosis factor–related apoptosis-inducing ligand(TRAIL) induces apoptosis of tumor cells but not normal cells;its role in normal nontransformed tissues is unknown. We reporthere that chronic blockade of TRAIL in mice exacerbated autoimmunearthritis, and that intraarticular TRAIL gene transfer amelioratedthe disease. In vivo, TRAIL blockade led to profound hyperproliferationof synovial cells and arthritogenic lymphocytes and heightenedthe production of cytokines and autoantibodies. In vitro, TRAILinhibited DNA synthesis and prevented cell cycle progressionof lymphocytes. Interestingly, TRAIL had no effect on apoptosisof inflammatory cells either in vivo or in vitro. Thus, unlikeother members of the tumor necrosis factor superfamily, TRAILis a prototype inhibitor protein that inhibits autoimmune inflammationby blocking cell cycle progression.

Key Words: autoimmunity, inflammation, apoptosis, cytokine, TRAIL

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