title: Molecular mechanism of ER stress-induced gene expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in macrophages.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily, whose members are capable of inducing apoptosis and inflammation. Endoplasmic reticulum stress (ERS) plays a key role in immune surveillance in macrophages. TRAIL mRNA and protein expression have previously been detected in macrophages; however, whether ERS has any effects on TRAIL expression in macrophages has not yet been determined. Here, we demonstrate that thapsigargin (TG) and tunicamycin (TM), two ERS inducers activated macrophages were able to increase TRAIL mRNA and protein expression in RAW264.7 macrophages, the culture supernatant of THP-1 cells, and mouse peritoneal macrophages, indicating that ERS as a potent inducer of TRAIL transcription and expression in macrophages. This effect was blocked by the specific JNK inhibitor SP600125 and transcription factor AP-1 inhibitor SR 1130. Interestingly, at the molecular level, regulation of TRAIL expression by ERS was accompanied by a significant decrease in cytokine signaling suppressor 3 (SOCS3). SOCS3 siRNA clearly increased the expression of TRAIL mRNA and protein under ERS by activating the AP-1 components phosphorylated c-Jun and phosphorylated c-Fos in RAW264.7 cells. In contrast, over-expression of SOCS3 reversed ERS-induced TRAIL expression. These findings provide in vitro evidence that SOCS3 plays a critical negative role in the regulation of ERS-induced TRAIL expression via the Jun N-terminal kinase/AP-1 signaling pathway in macrophages.
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei, China.|Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei, China.|Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, China.
authors.forename: Yarui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei, China.|Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Li
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei, China.|Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, China.
authors.forename: Zhaolin
authors.initials: Z
authors.lastname: Chen
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei, China.|Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Li
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei, China.|Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei, China.|Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Ni
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei, China.|Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007157:Immunologic Surveillance; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; C106644:SOCS3 protein, human; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D018808:Transcription Factor AP-1
keywords: AP-1; ER stress; SOCS3; TRAIL; macrophages