HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Santiago, B. Articles by Pablos, J. L. Search for Related Content PubMed PubMed Citation Articles by Santiago, B. Articles by Pablos, J. L.

Intracellular Regulation of Fas-Induced Apoptosis in Human Fibroblasts by Extracellular Factors and Cycloheximide ¹

Begoña Santiago^*, María Galindo, Guillermo Palao^* and José L. Pablos^2,

^* Unidad de Investigación and Servicio de Reumatología, Hospital 12 de Octubre, Madrid, Spain

Fibroblasts play an important role in reparative and inflammatory processes by synthesizing extracellular matrix components and releasing growth factors and cytokines. Fibroblast apoptosis has been observed at the termination phase of reparative or fibrotic responses, but its regulation in this context is poorly known. We investigated the susceptibility of human dermal fibroblasts (DF) to Fas-induced apoptosis and its regulation by extracellular factors potentially involved in immune-mediated inflammation and repair. DF expressed all components of the Fas apoptotic pathway: surface Fas, Fas-associated protein with death domain, and caspase-8 proteins. However, Fas activation resulted in caspase-8 activation and apoptosis only in the presence of cycloheximide (CHX). DF constitutively expressed Fas-associated death domain-like IL-1-converting enzyme-like inhibitory protein (FLIP) that was drastically down-regulated by CHX. Exogenous growth factors, cytokines, and adherence to the extracellular matrix shifted the balance of FLIP-caspase-8 proteins and modified the susceptibility of DF to Fas- or Fas-CHX-induced apoptosis. Short-term serum deprivation, suspension culture, and pretreatment with IFN- or TNF- increased, whereas long-term serum-free culture and pretreatment with TGF- or IL-10 decreased the apoptotic susceptibility of DF. Surface Fas expression was only modified by TNF- and IFN-, whereas all studied factors modified FLIP-caspase-8 protein expression, consistently with their pro- or antiapoptotic effects. Antisense FLIP oligonucleotides prevented resistance to Fas-induced apoptosis in DF. FLIP-caspase-8 balance seems tightly regulated in fibroblasts by extracellular factors that determine their susceptibility to Fas- or Fas-CHX-induced apoptosis. Th1 and Th regulatory cytokines display opposite effects on fibroblast apoptosis that suggest that their pro- or antifibrotic effects involve direct effects on fibroblast survival.

This article has been cited by other articles:

				V. Juric, C.-C. Chen, and L. F. Lau Fas-Mediated Apoptosis Is Regulated by the Extracellular Matrix Protein CCN1 (CYR61) In Vitro and In Vivo Mol. Cell. Biol., June 15, 2009; 29(12): 3266 - 3279. [Abstract] [Full Text] [PDF]

				X. Y. Wang, J. G. Crowston, H. Zoellner, and P. R. Healey Interferon-{alpha} and Interferon-{gamma} Sensitize Human Tenon Fibroblasts to Mitomycin-C Invest. Ophthalmol. Vis. Sci., August 1, 2007; 48(8): 3655 - 3661. [Abstract] [Full Text] [PDF]

				T. R. Wilson, K. M. McLaughlin, M. McEwan, H. Sakai, K. M.A. Rogers, K. M. Redmond, P. G. Johnston, and D. B. Longley c-FLIP: A Key Regulator of Colorectal Cancer Cell Death Cancer Res., June 15, 2007; 67(12): 5754 - 5762. [Abstract] [Full Text] [PDF]

				M. S. Bharhani, R. Borojevic, S. Basak, E. Ho, P. Zhou, and K. Croitoru IL-10 protects mouse intestinal epithelial cells from Fas-induced apoptosis via modulating Fas expression and altering caspase-8 and FLIP expression. Am J Physiol Gastrointest Liver Physiol, November 1, 2006; 291(5): G820 - G829. [Abstract] [Full Text] [PDF]

				M.-S. Lee, S.-A. Yoo, C.-S. Cho, P.-G. Suh, W.-U. Kim, and S. H. Ryu Serum Amyloid A Binding to Formyl Peptide Receptor-Like 1 Induces Synovial Hyperplasia and Angiogenesis J. Immunol., October 15, 2006; 177(8): 5585 - 5594. [Abstract] [Full Text] [PDF]

				R. Kim, M. Emi, K. Tanabe, and K. Arihiro Tumor-Driven Evolution of Immunosuppressive Networks during Malignant Progression Cancer Res., June 1, 2006; 66(11): 5527 - 5536. [Abstract] [Full Text] [PDF]

				S. K. Frankel, G. P. Cosgrove, S.-I. Cha, C. D. Cool, M. W. Wynes, B. L. Edelman, K. K. Brown, and D. W. H. Riches TNF-{alpha} Sensitizes Normal and Fibrotic Human Lung Fibroblasts to Fas-Induced Apoptosis Am. J. Respir. Cell Mol. Biol., March 1, 2006; 34(3): 293 - 304. [Abstract] [Full Text] [PDF]

				J. da Silva Correia, Y. Miranda, N. Austin-Brown, J. Hsu, J. Mathison, R. Xiang, H. Zhou, Q. Li, J. Han, and R. J. Ulevitch Nod1-dependent control of tumor growth PNAS, February 7, 2006; 103(6): 1840 - 1845. [Abstract] [Full Text] [PDF]

				S.-M. Park, S. Kim, J.-S. Choi, D.-Y. Hur, W.-J. Lee, M.-S. Lee, J. Choe, and T. H. Lee TGF-{beta} Inhibits Fas-Mediated Apoptosis of a Follicular Dendritic Cell Line by Down-Regulating the Expression of Fas and Caspase-8: Counteracting Role of TGF-{beta} on TNF Sensitization of Fas-Mediated Apoptosis J. Immunol., May 15, 2005; 174(10): 6169 - 6175. [Abstract] [Full Text] [PDF]