The Journal of Experimental Medicine
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Published online 3 April 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 Songa, Yiguang Chena, Rüdiger Gökea, Andreas Wilmena, Cheryl Seidela, Alexandra Gökea, Brendan Hilliarda, and Youhai Chena

a Department of Molecular and Cellular Engineering, Institute for Human Gene Therapy, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
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 19104.215-573-2275215-898-4671

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 report here that chronic blockade of TRAIL in mice exacerbated autoimmune arthritis, and that intraarticular TRAIL gene transfer ameliorated the disease. In vivo, TRAIL blockade led to profound hyperproliferation of synovial cells and arthritogenic lymphocytes and heightened the production of cytokines and autoantibodies. In vitro, TRAIL inhibited DNA synthesis and prevented cell cycle progression of lymphocytes. Interestingly, TRAIL had no effect on apoptosis of inflammatory cells either in vivo or in vitro. Thus, unlike other members of the tumor necrosis factor superfamily, TRAIL is a prototype inhibitor protein that inhibits autoimmune inflammation by blocking cell cycle progression.

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

Abbreviations used in this paper: Ad, adenovirus; AICD, activation-induced cell death; ANOVA, analysis of variance; BrdU, bromodeoxyuridine; DR, death receptor; DcR, decoy receptor; HE, hematoxylin and eosin; HSA, human serum albumin; L, ligand; NF, nuclear factor; s, soluble; TRAIL, tumor necrosis factor–related apoptosis-inducing ligand.

© 2000 The Rockefeller University Press


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