title: A Study of TNF Pathway Activation in Schizophrenia and Bipolar Disorder in Plasma and Brain Tissue.
abstract: A proinflammatory imbalance in the tumor necrosis factor (TNF) system may contribute to the pathogenesis of schizophrenia (SCZ) and bipolar disorders (BDs) and related comorbidities. We investigated the relative distribution of TNF-related molecules in blood and dorsolateral prefrontal cortex (DLPFC) in these disorders.
  
  
  
  We measured plasma levels of TNF, soluble TNF receptor 1 (sTNFR1), soluble TNF receptor 2 (sTNFR2), and a disintegrin and metalloprotease-17 (ADAM17) using enzyme immunoassays and calculated the TNF/sTNFRs ratio (TNF/sTNFR1+sTNFR2) in a sample of 816 SCZ and BD spectrum patients and 624 healthy controls (HCs). TNF, TNFRSF1A (TNFR1), TNFRSF1B (TNFR2), and ADAM17 mRNA levels were determined in whole blood, and postmortem DLPFC obtained from an independent cohort (n = 80 SCZ, n = 44 BD, and n = 86 HC).
  
  
  
  In peripheral blood, we show increased TNF-related measures in patients compared to HC, with an increased TNF/sTNFRs ratio (p = 6.00 × 10-5), but decreased TNF mRNA expression (p = 1 × 10-4), with no differences between SCZ and BD. Whole blood ADAM17 mRNA expression was markedly higher in BD vs SCZ patients (p = 1.40 × 10-14) and vs HC (p = 1.22 × 10-8). In postmortem DLPFC, we found no significant differences in mRNA expression of TNF pathway genes between any groups.
  
  
  
  SCZ and BD patients have increased plasma TNF pathway markers without corresponding increase in blood cell gene expression. ADAM17 expression in leukocytes is markedly different between the two disorders, while alterations in TNF-related gene expression in DLPFC are uncertain. Further studies are necessary to elucidate the aberrant regulation of the TNF pathway in severe mental disorders.
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research Building 49, Oslo University Hospital, Ullevål Kirkeveien 166, PO Box 4956 Nydalen 0424, Oslo, Norway.|Division of Mental Health and Addiction, Møre and Romsdal Health Trust, Kristiansund, Norway.
authors.forename: Eva Zsuzsanna
authors.initials: EZ
authors.lastname: Hoseth
authors.affiliation: Research Institute for Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Institute of Clinical Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.|K.G. Jensen inflammatory Research Center, University of Oslo, Oslo, Norway.
authors.forename: Thor
authors.initials: T
authors.lastname: Ueland
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research Building 49, Oslo University Hospital, Ullevål Kirkeveien 166, PO Box 4956 Nydalen 0424, Oslo, Norway.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Dieset
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Birnbaum
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD.
authors.forename: Joo Heon
authors.initials: JH
authors.lastname: Shin
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD.|Departments of Psychiatry and Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Joel Edward
authors.initials: JE
authors.lastname: Kleinman
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD.|Departments of Psychiatry and Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Thomas Michael
authors.initials: TM
authors.lastname: Hyde
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research Building 49, Oslo University Hospital, Ullevål Kirkeveien 166, PO Box 4956 Nydalen 0424, Oslo, Norway.
authors.forename: Ragni Helene
authors.initials: RH
authors.lastname: Mørch
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research Building 49, Oslo University Hospital, Ullevål Kirkeveien 166, PO Box 4956 Nydalen 0424, Oslo, Norway.
authors.forename: Sigrun
authors.initials: S
authors.lastname: Hope
authors.affiliation: Research Institute for Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Tove
authors.initials: T
authors.lastname: Lekva
authors.affiliation: Research Institute for Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Aurelija Judita
authors.initials: AJ
authors.lastname: Abraityte
authors.affiliation: Research Institute for Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Annika E
authors.initials: AE
authors.lastname: Michelsen
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research Building 49, Oslo University Hospital, Ullevål Kirkeveien 166, PO Box 4956 Nydalen 0424, Oslo, Norway.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Melle
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research Building 49, Oslo University Hospital, Ullevål Kirkeveien 166, PO Box 4956 Nydalen 0424, Oslo, Norway.|Department of Psychology, University of Oslo, Oslo, Norway.
authors.forename: Lars Tjelta
authors.initials: LT
authors.lastname: Westlye
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research Building 49, Oslo University Hospital, Ullevål Kirkeveien 166, PO Box 4956 Nydalen 0424, Oslo, Norway.|Department of Psychology, University of Oslo, Oslo, Norway.
authors.forename: Torill
authors.initials: T
authors.lastname: Ueland
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.|NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Srdjan
authors.initials: S
authors.lastname: Djurovic
authors.affiliation: Research Institute for Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Institute of Clinical Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD.|Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD.|Departments of Psychiatry and Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research Building 49, Oslo University Hospital, Ullevål Kirkeveien 166, PO Box 4956 Nydalen 0424, Oslo, Norway.
authors.forename: Ole Andreas
authors.initials: OA
authors.lastname: Andreassen
mesh_terms: D000072198:ADAM17 Protein / Q000097:blood / Q000378:metabolism*; D000328:Adult; D001714:Bipolar Disorder / Q000097:blood / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood / Q000378:metabolism*; D012559:Schizophrenia / Q000097:blood / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506235:TNFRSF1A protein, human; C415902:TNFRSF1B protein, human; D014409:Tumor Necrosis Factor-alpha; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
keywords: DLPFC; cytokines; mRNA; postmortem; working memory