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TNF- Sensitizes Normal and Fibrotic Human Lung Fibroblasts to Fas-Induced Apoptosis

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

Correspondence and requests for reprints should be addressed to David W. H. Riches, Ph.D., Program in Cell Biology, D-405, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. 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 (1) increased migration of a circulating pool of fibrocytes, (2) cell proliferation, and (3) 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 proinflammatory cytokines TNF- and IFN-. Herein, we show that the basal resistance of lung fibroblasts and myofibroblasts to Fas-induced apoptosis is overcome by sensitization with TNF-. IFN- did not sensitize cells to Fas-induced apoptosis, but exhibited synergistic activity with TNF-. Sensitization by TNF- was observed in MRC-5 cells and in fibroblasts and myofibroblasts from normal and fibrotic human lung, suggesting that 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.

Key Words: fibroblast • TNF- • Fas • apoptosis • pulmonary fibrosis

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