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

Wynes, Murry W.; Edelman, Benjamin; Kostyk, Amanda G.; Edwards, Michael G.; Coldren, Christopher D.; Groshong, Steve D.; Cosgrove, Gregory P.; Redente, Elizabeth F.; Bamberg, Alison; Brown, Kevin K.; Reisdorph, Nichole; Keith, Rebecca C.; Frankel, Stephen K.; Riches, David W. H.

doi:10.4049/jimmunol.1100447

Cited by 63 publications

(72 citation statements)

References 61 publications

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“…The mechanisms accounting for the increased resistance to apoptosis in IPF fibroblasts have not been completely defined. Studies show that decreased cell surface expression of the Fas receptor is likely to contribute because increasing Fas receptor expression is sufficient to sensitize these cells to Fasinduced apoptosis (33,34,36). Consistently, we have shown that PGE 2 enhances Fas-mediated apoptosis in lung fibroblasts while increasing expression of the Fas receptor (10).…”

Section: Discussionsupporting

confidence: 71%

“…Fibroblasts have an inherent resistance to Fas-mediated apoptosis in vitro, although the response to Fas activation can be enhanced by (1) treatment with the protein translation inhibitor cycloheximide, (2) treatment with the antifibrotic mediator PGE 2 , or (3) treatment with proinflammatory cytokines (10,11,(33)(34)(35)(36). We assessed apoptosis in normal lung fibroblast cell lines (IMR-90 and CCL-210) and patient-derived primary fibroblasts from normal and IPF tissue after exposure to a Fas-activating antibody (Fas-Ab) with and without cycloheximide.…”

Section: Ipf Lung Fibroblasts Have Decreased Susceptibility To Fas-mementioning

confidence: 99%

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X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis

Ajayi

Sisson

Higgins

et al. 2013

Am J Respir Cell Mol Biol

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The accumulation of apoptosis-resistant fibroblasts within fibroblastic foci is a characteristic feature of idiopathic pulmonary fibrosis (IPF), but the mechanisms underlying apoptosis resistance remain unclear. A role for the inhibitor of apoptosis (IAP) protein family member X-linked inhibitor of apoptosis (XIAP) has been suggested by prior studies showing that (1) XIAP is localized to fibroblastic foci in IPF tissue and (2) prostaglandin E 2 suppresses XIAP expression while increasing fibroblast susceptibility to apoptosis. Based on these observations, we hypothesized that XIAP would be regulated by the profibrotic mediators transforming growth factor (TGF)b-1 and endothelin (ET)-1 and that increased XIAP would contribute to apoptosis resistance in IPF fibroblasts. To address these hypotheses, we examined XIAP expression in normal and IPF fibroblasts at baseline and in normal fibroblasts after treatment with TGF-b1 or ET-1. The role of XIAP in the regulation of fibroblast susceptibility to Fas-mediated apoptosis was examined using functional XIAP antagonists and siRNA silencing. In concordance with prior reports, fibroblasts from IPF lung tissue had increased resistance to apoptosis compared with normal lung fibroblasts. Compared with normal fibroblasts, IPF fibroblasts had significantly but heterogeneously increased basal XIAP expression. Additionally, TGF-b1 and ET-1 induced XIAP protein expression in normal fibroblasts. Inhibition or silencing of XIAP enhanced the sensitivity of lung fibroblasts to Fasmediated apoptosis without causing apoptosis in the absence of Fas activation. Collectively, these findings support a mechanistic role for XIAP in the apoptosis-resistant phenotype of IPF fibroblasts.Keywords: myofibroblast; idiopathic pulmonary fibrosis; inhibitor of apoptosis; lung fibrosis; apoptosis Mesenchymal cells display a dynamic spectrum of phenotypes ranging between an undifferentiated state (fibroblast) and a differentiated state (myofibroblast) (1, 2). Although these effector cells are essential for the homeostatic reestablishment of normal architecture and function after tissue injury, the persistence of these cells is associated with fibrosis (3, 4). The resolution phase of normal wound repair coincides with the reduction of fibroblast numbers by apoptosis, but the triggers of apoptosis in normal wound repair and the mechanisms underlying the persistence of fibroblasts during fibrotic wound repair remain poorly understood (5, 6). The profibrotic mediators transforming growth factor (TGF)b-1 and endothelin (ET)-1 have been found to promote resistance to apoptotic stimuli in fibroblasts, and the antifibrotic lipid mediator prostaglandin (PG)E 2 has been shown to increase the responsiveness of these cells to apoptotic stimuli, supporting a role for dysregulation of fibroblast apoptosis in the pathogenesis of fibrosis (7-12).Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of unknown etiology that is characterized by progressive alveolar fibrosis (13,14). The overall prognosis of patie...

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Section: Discussionsupporting

confidence: 71%

Section: Ipf Lung Fibroblasts Have Decreased Susceptibility To Fas-mementioning

confidence: 99%

X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis

Ajayi

Sisson

Higgins

et al. 2013

Am J Respir Cell Mol Biol

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“…The MRC5 cell line has been used for studying TGF-β signaling and fibrosis (47)(48)(49)(50)(51). The A549 cell line is frequently used in research regarding alveolar type II epithelial cells (52)(53)(54)(55).…”

Section: Activation Of `7 Nachr Promotes Transcription Of Fibrotic Gementioning

confidence: 99%

Deficiency of α7 Nicotinic Acetylcholine Receptor Attenuates Bleomycin-Induced Lung Fibrosis in Mice

Sun

Zhao

et al. 2017

Mol Med

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“…Myofibroblasts derived from patients with idiopathic lung fibrosis were shown to express Fas ligand and were capable of inducing apoptosis of epithelial cells. However, these myofibroblasts themselves appeared to be immuno-privileged and were resistant to Fas-induced killing (28,47,85). These findings, coupled to known alterations in GSH homeostasis in the fibrotic lung suggest that altered redox-based regulation of the apoptotic cascade may fuel the pathogenesis of lung fibrosis (Fig.…”

Section: S-glutathionylation Death Receptors and Lung Fibrosismentioning

confidence: 66%

Redox-Based Regulation of Apoptosis: S-Glutathionylation As a Regulatory Mechanism to Control Cell Death

Anathy

Roberson

Guala

et al. 2012

Antioxidants & Redox Signaling

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Significance: Redox-based signaling governs a number of important pathways in tissue homeostasis. Consequently, deregulation of redox-controlled processes has been linked to a number of human diseases. Among the biological processes regulated by redox signaling, apoptosis or programmed cell death is a highly conserved process important for tissue homeostasis. Apoptosis can be triggered by a wide variety of stimuli, including death receptor ligands, environmental agents, and cytotoxic drugs. Apoptosis has also been implicated in the etiology of many human diseases. Recent Advances: Recent discoveries demonstrate that redox-based changes are required for efficient activation of apoptosis. Among these redox changes, alterations in the abundant thiol, glutathione (GSH), and the oxidative post-translational modification, protein S-glutathionylation (PSSG) have come to the forefront as critical regulators of apoptosis. Critical Issues: Although redox-based changes have been documented in apoptosis and disease pathogenesis, the mechanistic details, whereby redox perturbations intersect with pathogenic processes, remain obscure. Future Directions: Further research will be needed to understand the context in which of the members of the death receptor pathways undergo ligand dependent oxidative modifications. Additional investigation into the interplay between oxidative modifications, redox enzymes, and apoptosis pathway members are also critically needed to improve our understanding how redoxbased control is achieved. Such analyses will be important in understanding the diverse chronic diseases. In this review we will discuss the emerging paradigms in our current understanding of redox-based regulation of apoptosis with an emphasis on S-glutathionylation of proteins and the enzymes involved in this important posttranslational modification. Antioxid. Redox Signal. 16,[496][497][498][499][500][501][502][503][504][505]

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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

Cited by 63 publications

References 61 publications

X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis

X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis

Deficiency of α7 Nicotinic Acetylcholine Receptor Attenuates Bleomycin-Induced Lung Fibrosis in Mice

Redox-Based Regulation of Apoptosis: S-Glutathionylation As a Regulatory Mechanism to Control Cell Death

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