title: Hepatitis C Virus E2 Protein Induces Upregulation of IL-8 Pathways and Production of Heat Shock Proteins in Human Thyroid Cells.
abstract: Thyroiditis is one of the most common extrahepatic manifestations of hepatitis C virus (HCV) infection. By binding to surface cell receptor CD81, HCV envelope glycoprotein E2 mediates entry of HCV into cells. Studies have shown that different viral proteins may individually induce host responses to infection. We hypothesized that HCV E2 protein binding to CD81 expressed on thyroid cells activates a cascade of inflammatory responses that can trigger autoimmune thyroiditis in susceptible individuals.
  
  
  
  Human thyroid cell lines ML-1 and human thyrocytes in primary cell culture were treated with HCV recombinant E2 protein. The expression of major proinflammatory cytokines was measured at the messenger RNA and protein levels. Next-generation transcriptome analysis was used to identify early changes in gene expression in thyroid cells induced by E2.
  
  
  
  HCV envelope protein E2 induced strong inflammatory responses in human thyrocytes, resulting in production of interleukin (IL)-8, IL-6, and tumor necrosis factor-α. Furthermore, the E2 protein induced production of several heat shock proteins including HSP60, HSP70p12A, and HSP10, in human primary thyrocytes. In thyroid cell line ML-1, RNA sequencing identified upregulation of molecules involved in innate immune pathways with high levels of proinflammatory cytokines and chemokines and increased expression of costimulatory molecules, specifically CD40, known to be a major thyroid autoimmunity gene.
  
  
  
  Our data support a key role for HCV envelope protein E2 in triggering thyroid autoimmunity through activation of cytokine pathways by bystander mechanisms.
authors.affiliation: Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Aker, 0586 Oslo, Norway.|Department of Pediatrics, Oslo University Hospital, Ullevål, 0450 Oslo, Norway.
authors.forename: Sara Salehi
authors.initials: SS
authors.lastname: Hammerstad
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York 10461.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Stefan
authors.affiliation: Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267.
authors.forename: Jason
authors.initials: J
authors.lastname: Blackard
authors.affiliation: Department of Surgery, Division of Surgical Oncology.
authors.forename: Randall P
authors.initials: RP
authors.lastname: Owen
authors.affiliation: Department of Medicine, Division of Endocrinology, and.
authors.forename: Hanna J
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York 10461.
authors.forename: Erlinda
authors.initials: E
authors.lastname: Concepcion
authors.affiliation: Department of Medicine Bioinformatics Core, Mount Sinai Hospital, Icahn School of Medicine, New York, New York 10029.
authors.forename: Zhengzi
authors.initials: Z
authors.lastname: Yi
authors.affiliation: Department of Medicine Bioinformatics Core, Mount Sinai Hospital, Icahn School of Medicine, New York, New York 10029.
authors.forename: Weijia
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York 10461.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Tomer
mesh_terms: D015551:Autoimmunity / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D018835:Chaperonin 10 / Q000378:metabolism; D018834:Chaperonin 60 / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism*; D000072637:Thyroid Epithelial Cells / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000276:immunology*
chemical_list: C508606:CXCL8 protein, human; D018835:Chaperonin 10; D018834:Chaperonin 60; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus