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Published ahead of print on November 4, 2005, doi:10.1165/rcmb.2005-0155OC

Am. J. Respir. Cell Mol. Biol., Volume 34, Number 3, March 2006, 293-304

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Submitted on April 26, 2005
Revised on November 4, 2005

TNF-{alpha} Sensitizes Normal and Fibrotic Human Lung Fibroblasts to Fas-induced Apoptosis

Stephen K Frankel1, Gregory P Cosgrove1, Seung-Ick Cha2, Carlyne D Cool2, Murry W Wynes3, Benjamin L Edelman4, Kevin K Brown1, and David W.H. Riches5*

1 Department of Medicine, Interstitial Lung Disease Program, National Jewish Medical and Research Center, Denver, CO, USA; Department of Immunology, University of Colorado Health Sciences Center, Denver, CO, USA, 2 Department of Medicine, Interstitial Lung Disease Program, National Jewish Medical and Research Center, Denver, CO, USA, 3 Department of Pediatrics, Program in Lung in Cell Biology, National Jewish Medical and Research Center, Denver, CO, USA; Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO, USA, 4 Department of Pediatrics, Program in Lung in Cell Biology, National Jewish Medical and Research Center, Denver, CO, USA, 5 Department of Pediatrics, Program in Lung in Cell Biology, National Jewish Medical and Research Center, Denver, CO, USA; Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO, USA; Department of Immunology, University of Colorado Health Sciences Center, Denver, CO, USA

* To whom correspondence should be addressed. E-mail: richesd{at}njc.org.

Pulmonary accumulation of fibroblasts and myofibroblasts in idiopathic pulmonary fibrosis/usual interstitial pneumonia (IFP/UIP) has been linked to (i) increased migration of a circulating pool of fibrocytes, (ii) cell proliferation and (iii) resistance to apoptosis. The mechanism of physiologic apoptosis of lung fibroblasts is poorly understood. Using normal and fibrotic human lung fibroblasts and the human lung fibroblast cell line, MRC-5, we examined the regulation of Fas-induced apoptosis by the pro-inflammatory cytokines TNF-{alpha} and IFN-{gamma}. Herein, we show that the basal resistance of lung fibroblasts and myofibroblasts to Fas-induced apoptosis is overcome by sensitization with TNF-{alpha}. IFN-{gamma} did not sensitize cells to Fas-induced apoptosis, but exhibited synergistic activity with TNF-{alpha}. Sensitization by TNF-{alpha} was observed in MRC-5 cells and in fibroblasts and myofibroblasts from normal and fibrotic human lung origin suggesting this represents a conserved mechanism to engage Fas-induced apoptosis. The mechanism of sensitization was localized at the level of recruitment of the adapter protein, FADD, to the cytoplasmic domain of Fas. Collectively, these findings suggest that fibroblast apoptosis involves two steps, sensitization and induction, and that inadequate pulmonary inflammation in IPF/UIP may favor fibroblast accumulation by reducing sensitization to apoptosis.




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