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J Biol Chem, Vol. 274, Issue 3, 1479-1486, January 15, 1999

TL1, a Novel Tumor Necrosis Factor-like Cytokine, Induces Apoptosis in Endothelial Cells
INVOLVEMENT OF ACTIVATION OF STRESS PROTEIN KINASES (STRESS-ACTIVATED PROTEIN KINASE AND p38 MITOGEN-ACTIVATED PROTEIN KINASE) AND CASPASE-3-LIKE PROTEASE

Tian-Li Yue, Jian Ni^¶, Anne M. Romanic, Juan-Li Gu, Paul Keller, Chuanlin Wang, Sanjay Kumar^**, Guo-liang Yu^¶, Timothy K. Hart, Xinkang Wang, Zhengui Xia^§§, Walter E. DeWolf Jr., and Giora Z. Feuerstein

From the Departments of  Cardiovascular Pharmacology,  Molecular Recognition,  Toxicology, and ^** Bone and Cartilage, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19046, the ^§§ Department of Environmental Health, University of Washington, Seattle, Washington 98195, and ^¶ Human Genome Sciences, Inc., Rockville, Maryland 20850

TL1 is a recently discovered novel member of the tumor necrosis factor (TNF) cytokine family. TL1 is abundantly expressed in endothelial cells, but its function is not known. The present study was undertaken to explore whether TL1 induces apoptosis in endothelial cells and, if so, to explore its mechanism of action. Cultured bovine pulmonary artery endothelial cells (BPAEC) exposed to TL1 showed morphological (including ultrastructural) and biochemical features characteristic of apoptosis. TL1-induced apoptosis in BPAEC was a time- and concentration-dependent process (EC₅₀ = 72 ng/ml). The effect of TL1 was not inhibited by soluble TNF receptors 1 or 2. TL1 up-regulated Fas expression in BPAEC at 8 and 24 h after treatment, and significantly activated stress-activated protein kinase (SAPK) and p38 mitogen-activated protein kinase (p38 MAPK). The peak activities of SAPK and p38 MAPK in TL1-treated BPAEC were increased by 9- and 4-fold, respectively. TL1-induced apoptosis in the BPAEC was reduced by expression of a dominant-interfering mutant of c-Jun (62.8%, p < 0.05) or by a specific p38 inhibitor, SB203580 (1-10 µM) dose-dependently. TL1 also activated caspases in BPAEC, and TL1-induced apoptosis in BPAEC was significantly attenuated by the caspase inhibitor, ZVAD-fluromethyl-ketone. The major component activated by TL1 in BPAEC was caspase-3, which was based on substrate specificity and immunocytochemical analysis. These findings suggest that TL1 may act as an autocrine factor to induce apoptosis in endothelial cells via activation of multiple signaling pathways, including stress protein kinases as well as certain caspases.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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