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Regulation and role of the pro-apoptotic transcription factor CHOP in Idiopathic Pulmonary Fibrosis

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal interstitial lung disease characterized by alveolar epithelial cell type II (AECII) injury and enhanced fibroblast/myofibroblast proliferation. Recent data show that maladaptive endoplasmic reticulum (ER)-stress leading to AECII apoptosis could play a key role in IPF, although it is still unclear how precisely such response is initiated and signalled. C/EBP homologous protein (CHOP) has been suggested to contribute to a maladaptive ER-stress response in general and has been found to be induced and to be translocated into the nucleus of AECII in IPF in particular. We here show for the first time a novel mechanism for the regulation of CHOP expression during ER-stress in AECII via AP-1 and c-Ets-1. We found these two transcription factors to be up-regulated in AECII under ER-stress conditions and to interact with each other to jointly bind to the CHOP promoter, thereby inducing CHOP gene expression. Moreover, we show for the first time that singular CHOP overexpression in vitro and in vivo is indeed capable of inducing apoptosis of AECII and, consequently, lung fibroblast proliferation and up-regulation of pro-fibrotic markers. We therefore believe that CHOP plays a key role in AEC injury and consecutive fibrosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE87298 | GEO | 2017/09/23

SECONDARY ACCESSION(S): PRJNA344083

REPOSITORIES: GEO

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Project description:The activated fibroblast is the central effector cell for the progressive fibrotic process that characterizes idiopathic pulmonary fibrosis (IPF). An understanding of the genomic phenotype of this cell in isolation is essential to the understanding of disease pathogenesis and is integral to strategizing therapeutic trials. Employing a unique technique that minimizes cellular phenotypic alterations, we characterized the genomic phenotype of non-cultured pulmonary fibroblasts from the lungs of patients with advanced IPF. This approach revealed several novel genes and pathways previously unreported in IPF fibroblasts. Specifically, we demonstrate altered expression in proteasomal constituents, ubiquitination mediators, the Wnt pathway and several cell cycle regulators suggestive of loss of normal cell cycle controls. The pro-inflammatory cytokine CXCL12 was also up-regulated which may provide a mechanism for fibrocytes’ recruitment, while up-regulated oncogenic KIT may promote fibroblast over proliferation. Paradoxically, pro-apoptotic inducers such as death inducing ligand TRAIL (TNFSF10) and pro-apoptotic Bax were also up-regulated. This comprehensive description of altered gene expression within IPF fibroblasts sheds further light on the complex interactions that characterize IPF. Further studies including therapeutic interventions directed at these pathways hold promise for the treatment of this devastating disease. 58 samples of total RNA isolated from 12 lungs of patients with end-stage idiopathic pulmonary fibrosis and 6 donors of normal lungs (controls) who were designated brain dead, non-diseased donors whose lungs failed criteria for transplantation and who were organ donors for research. RNA extraction followed the Qiagen RNeasy Kit using QIshredder columns for shredding of DNA contiminants. Experimental/control samples were amplified amino-allylated RNA labeled with Cy5 and Stratagene Reference RNA was amplified and amino-allylated and labeled with Cy3. Amplification was one round using Ambion MessageAmp II kit with amino-allylated UTP according to the protocol of the Duke University Institute for Genome Sciences and Policy. Amplification and amino-allylation of the Stratagene Reference RNA and Hybridization of Reference with patient samples and controls was done by the Duke Institute for Genomic Sciences and Policy.

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Regulation and role of the pro-apoptotic transcription factor CHOP in Idiopathic Pulmonary Fibrosis

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