title: Increased cell surface Fas expression is necessary and sufficient to sensitize lung fibroblasts to Fas ligation-induced apoptosis: implications for fibroblast accumulation in idiopathic pulmonary fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF) is associated with the accumulation of collagen-secreting fibroblasts and myofibroblasts in the lung parenchyma. Many mechanisms contribute to their accumulation, including resistance to apoptosis. In previous work, we showed that exposure to the proinflammatory cytokines TNF-α and IFN-γ reverses the resistance of lung fibroblasts to apoptosis. In this study, we investigate the underlying mechanisms. Based on an interrogation of the transcriptomes of unstimulated and TNF-α- and IFN-γ-stimulated primary lung fibroblasts and the lung fibroblast cell line MRC5, we show that among Fas-signaling pathway molecules, Fas expression was increased ∼6-fold in an NF-κB- and p38(mapk)-dependent fashion. Prevention of the increase in Fas expression using Fas small interfering RNAs blocked the ability of TNF-α and IFN-γ to sensitize fibroblasts to Fas ligation-induced apoptosis, whereas enforced adenovirus-mediated Fas overexpression was sufficient to overcome basal resistance to Fas-induced apoptosis. Examination of lung tissues from IPF patients revealed low to absent staining of Fas in fibroblastic cells of fibroblast foci. Collectively, these findings suggest that increased expression of Fas is necessary and sufficient to overcome the resistance of lung fibroblasts to Fas-induced apoptosis. Our findings also suggest that approaches aimed at increasing Fas expression by lung fibroblasts and myofibroblasts may be therapeutically relevant in IPF.
authors.affiliation: Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO 80206, USA.
authors.forename: Murry W
authors.initials: MW
authors.lastname: Wynes
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Edelman
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Kostyk
authors.forename: Michael G
authors.initials: MG
authors.lastname: Edwards
authors.forename: Christopher
authors.initials: C
authors.lastname: Coldren
authors.forename: Steve D
authors.initials: SD
authors.lastname: Groshong
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Cosgrove
authors.forename: Elizabeth F
authors.initials: EF
authors.lastname: Redente
authors.forename: Alison
authors.initials: A
authors.lastname: Bamberg
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Brown
authors.forename: Nichole
authors.initials: N
authors.lastname: Reisdorph
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Keith
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Frankel
authors.forename: David W H
authors.initials: DW
authors.lastname: Riches
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D053222:Fas Ligand Protein / Q000096:biosynthesis / Q000235:genetics; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D008137:Longitudinal Studies; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D011446:Prospective Studies; D011658:Pulmonary Fibrosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*; D019014:fas Receptor / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics
chemical_list: C491901:FAS protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C491899:Fas protein, mouse; C505658:Fasl protein, mouse; D019014:fas Receptor