Media type: E-Article Title: TNF‐α in vivo stimulates apoptosis in fibroblasts through caspase‐8 activation and modulates the expression of pro‐apoptotic genes Contributor: Alikhani, Mani; Alikhani, Zoubin; Raptis, Markos; Graves, Dana T. Published: Wiley, 2004 Published in: Journal of Cellular Physiology, 201 (2004) 3, Seite 341-348 Language: English DOI: 10.1002/jcp.20067 ISSN: 0021-9541; 1097-4652 Origination: Footnote: Description: AbstractApoptosis of matrix producing cells is common among many inflammatory diseases. The goal of the present study was to examine the apoptotic effects of tumor necrosis factor‐α (TNF‐α) on fibroblastic cells in vivo and to investigate the role of different caspases in this process. This was accomplished in vivo by subcutaneous injection of TNF‐α in mice. The direct effects of TNF‐α on fibroblast apoptosis were studied in vitro with normal diploid human fibroblasts. The results indicate that TNF‐α in vivo induces apoptosis of fibroblasts. By RNase protection assay, we demonstrated that TNF‐α stimulates expression of 12 apoptotic genes. Fluorometric studies demonstrated that TNF‐α in vivo predominantly increased caspase‐8 and ‐3 activity and by use of specific inhibitors, the activation of caspase‐3 was shown to be initiated by caspase‐8 with only a minor contribution from caspase‐9. Thus, TNF‐α acts to modulate the expression of many genes that favors apoptosis of fibroblastic cells, which is dependent mostly upon signaling through caspase‐8. © 2004 Wiley‐Liss, Inc.