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Molecular and Cellular Biology, February 2002, p. 724-736, Vol. 22, No. 3
0270-7306/01/$04.00+0     DOI: 10.1128/MCB.22.3.724-736.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Induces Caspase-Dependent Interleukin-8 Expression and Apoptosis in Human Astroglioma Cells

Chulhee Choi,^1* Olaf Kutsch,¹ Jinseu Park,^1, Tong Zhou,² Dai-Wu Seol,³ and Etty N. Benveniste¹

Departments of Cell Biology,¹ Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294,² Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261³

Received 19 June 2001/ Returned for modification 30 July 2001/ Accepted 25 October 2001

Among the tumor necrosis factor (TNF) family of cytokines, FasL and TNF-related apoptosis-inducing ligand (TRAIL) are known to induce cell death via caspase activation. Recently, other biological functions of these death ligands have been postulated in vitro and in vivo. It was previously shown that Fas ligation induces chemokine expression in human glioma cells. In this study, we investigated whether the TRAIL-DR5 system transduces signals similar to those induced by other TNF family ligands and receptors. To address this issue, two human glioma cell lines, CRT-MG and U87-MG, were used, and an agonistic antibody against DR5 (TRA-8) and human recombinant TRAIL were used to ligate DR5. We demonstrate that DR5 ligation by either TRAIL or TRA-8 induces two functional outcomes, apoptosis and expression of the chemokine interleukin-8 (IL-8); the nonspecific caspase inhibitor Boc-D-Fmk blocks both TRAIL-mediated cell death and IL-8 production; the caspase 3-specific inhibitor z-DEVD-Fmk suppresses TRAIL-mediated apoptosis but not IL-8 induction; caspase 1- and 8-specific inhibitors block both TRAIL-mediated cell death and IL-8 production; and DR5 ligation by TRAIL mediates AP-1 and NF-B activation, which can be inhibited by caspase 1- and 8-specific inhibitors. These findings collectively indicate that DR5 ligation on human glioma cells leads to apoptosis and that the activation of AP-1 and NF-B leads to the induction of IL-8 expression; these responses are dependent on caspase activation. Therefore, the TRAIL-DR5 system has a role not only as an inducer of apoptotic cell death but also as a tranducer for proinflammatory and angiogenic signals in human brain tumors.

Present address: Department of Genetic Engineering, Division of Life Science, College of Natural Science, Hallym University, Chunchon 200-702, Korea.

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