title: Type I interferon-mediated skewing of the serotonin synthesis is associated with severe disease in systemic lupus erythematosus.
abstract: Serotonin, a highly pro-inflammatory molecule released by activated platelets, is formed by tryptophan. Tryptophan is also needed in the production of kynurenine, a process mediated by the type I interferon (IFN)-regulated rate-limiting enzyme indoleamine 2,3-dioxygenase (IDO). The aim of this study was to investigate levels of serotonin in patients with the autoimmune disease systemic lupus erythematosus (SLE), association to clinical phenotype and possible involvement of IDO in regulation of serotonin synthesis. Serotonin levels were measured in serum and plasma from patients with SLE (n=148) and healthy volunteers (n=79) by liquid chromatography and ELISA, as well as intracellularly in platelets by flow cytometry. We found that SLE patients had decreased serotonin levels in serum (p=0.01) and platelets (p<0.0001) as compared to healthy individuals. SLE patients with ongoing type I IFN activity, as determined by an in-house reporter assay, had decreased serum levels of serotonin (p=0.0008) as well as increased IDO activity (p<0.0001), as determined by the kynurenine/tryptophan ratio measured by liquid chromatography. Furthermore, SLE sera induced IDO expression in WISH cells in a type I IFN-dependent manner (p=0.008). Also platelet activation contributed to reduce overall availability of serotonin levels in platelets and serum (p<0.05). Decreased serum serotonin levels were associated with severe SLE with presence of anti-dsDNA antibodies and nephritis. In all, reduced serum serotonin levels in SLE patients were related to severe disease phenotype, including nephritis, suggesting involvement of important immunopathological processes. Further, our data suggest that type I IFNs, present in SLE sera, are able to up-regulate IDO expression, which may lead to decreased serum serotonin levels.
authors.affiliation: Department of Clinical Sciences Lund, Section of Rheumatology, Lund University and Skåne University Hospital, Lund, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: Lood
authors.affiliation: Department of Clinical Sciences Lund, Section of Rheumatology, Lund University and Skåne University Hospital, Lund, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Tydén
authors.affiliation: Department of Laboratory Medicine Lund, Section of Microbiology, Immunology and Glycobiology, Lund University, Lund, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Gullstrand
authors.affiliation: AnaMar AB, Lund, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Klint
authors.affiliation: AnaMar AB, Lund, Sweden.
authors.forename: Christina
authors.initials: C
authors.lastname: Wenglén
authors.affiliation: Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Christoffer T
authors.initials: CT
authors.lastname: Nielsen
authors.affiliation: Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Niels H H
authors.initials: NH
authors.lastname: Heegaard
authors.affiliation: Department of Clinical Sciences Lund, Section of Rheumatology, Lund University and Skåne University Hospital, Lund, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Jönsen
authors.affiliation: Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Robin
authors.initials: R
authors.lastname: Kahn
authors.affiliation: Department of Clinical Sciences Lund, Section of Rheumatology, Lund University and Skåne University Hospital, Lund, Sweden.
authors.forename: Anders A
authors.initials: AA
authors.lastname: Bengtsson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000974:Antibodies, Antinuclear / Q000097:blood; D001792:Blood Platelets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000097:blood*; D007370:Interferon Type I / Q000097:blood*; D007668:Kidney / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007737:Kynurenine / Q000097:blood; D008180:Lupus Erythematosus, Systemic / Q000097:blood* / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012701:Serotonin / Q000096:biosynthesis* / Q000097:blood; D012720:Severity of Illness Index; D014364:Tryptophan / Q000097:blood
chemical_list: D000974:Antibodies, Antinuclear; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007370:Interferon Type I; D012701:Serotonin; D007737:Kynurenine; D014364:Tryptophan