title: Induction of Apoptosis Coupled to Endoplasmic Reticulum Stress through Regulation of CHOP and JNK in Bone Marrow Mesenchymal Stem Cells from Patients with Systemic Lupus Erythematosus.
abstract: Previous studies indicated that bone marrow mesenchymal stem cells (BM-MSCs) from patients with systemic lupus erythematosus (SLE) exhibited the phenomenon of apoptosis. In this study, we aimed to investigate whether apoptosis of BM-MSCs from SLE patients were dysregulated. In this paper, endoplasmic reticulum stress (ERS) was evidenced by increased expression of phosphorylated protein kinase RNA-like ER kinase (PERK) and inositol-requiring protein-1 (IRE-1). We also found the activation of downstream target eukaryotic translation initiator factor 2α (eIF 2α) and CCAAT/enhancer-binding protein- (C/EBP-) homologous protein (CHOP) in BM-MSCs from SLE patients. Interestingly, we discovered that 4-phenylbutyric acid (4-PBA), a selective inhibitor of ERS, blocked the apoptosis of BM-MSCs from SLE patients and alleviated the level of Jun N-terminal kinase1/2 (JNK1/2) and CHOP. Furthermore, blockage of PERK signaling expression by siRNA not only significantly reduced the expression of CHOP, but also activated the anti-apoptotic regulator B-cell lymphoma-2 (Bcl-2). Blockage of IRE-1 or JNK1/2 by siRNA resulted in the decreased expression of JNK1/2 and proapoptosis protein Bcl-2 associated protein X (BAX). These results implicated that ERS-mediated apoptosis was a critical determinant of BM-MSCs from SLE patients.
authors.affiliation: Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong 226001, China.
authors.forename: Genkai
authors.initials: G
authors.lastname: Guo
authors.affiliation: Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong 226001, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Meng
authors.affiliation: Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong 226001, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Tan
authors.affiliation: Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong 226001, China.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College, Nantong University, Nantong 226001, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Nephrology, Affiliated Hospital of Nantong University, Nantong 226001, China.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong 226001, China.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Gu
mesh_terms: D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000502:physiology*; D001854:Bone Marrow Cells / Q000378:metabolism*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D016022:Case-Control Studies; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D004722:Endoribonucleases / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051742:Transcription Factor CHOP / Q000378:metabolism*; D055815:Young Adult; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C497249:DDIT3 protein, human; D015852:Eukaryotic Initiation Factor-2; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051742:Transcription Factor CHOP; C460640:EIF2AK3 protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D004722:Endoribonucleases