Eva Zsuzsanna Hoseth1,2, Thor Ueland3,4,5, Ingrid Dieset1, Rebecca Birnbaum6, Joo Heon Shin6, Joel Edward Kleinman6,7, Thomas Michael Hyde6,7, Ragni Helene Mørch1, Sigrun Hope1, Tove Lekva3, Aurelija Judita Abraityte3, Annika E Michelsen3, Ingrid Melle1, Lars Tjelta Westlye1,8, Torill Ueland1,8, Srdjan Djurovic9,10, Pål Aukrust3,4,6,11, Daniel R Weinberger6,7,12,13, Ole Andreas Andreassen1. 1. NORMENT, KG Jebsen Centre for Psychosis Research Building 49, Oslo University Hospital, Ullevål Kirkeveien 166, PO Box 4956 Nydalen 0424, Oslo, Norway. 2. Division of Mental Health and Addiction, Møre and Romsdal Health Trust, Kristiansund, Norway. 3. Research Institute for Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway. 4. Institute of Clinical Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway. 5. K.G. Jensen inflammatory Research Center, University of Oslo, Oslo, Norway. 6. Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD. 7. Departments of Psychiatry and Neurology, Johns Hopkins University School of Medicine, Baltimore, MD. 8. Department of Psychology, University of Oslo, Oslo, Norway. 9. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway. 10. NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway. 11. Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway. 12. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD. 13. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
Abstract
Objective: 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. Method: 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). Results: 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. Conclusions: 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.
Objective: 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. Method: 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). Results: 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. Conclusions: 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.
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