Lood Christian, Tydén Helena, Gullstrand Birgitta, Klint Cecilia, Wenglén Christina, Nielsen Christoffer T, Heegaard Niels H H, Jönsen Andreas, Kahn Robin, Bengtsson Anders A
Department of Clinical Sciences Lund, Section of Rheumatology, Lund University and Skåne University Hospital, Lund, Sweden.
Department of Laboratory Medicine Lund, Section of Microbiology, Immunology and Glycobiology, Lund University, Lund, Sweden.
PLoS One. 2015 Apr 21;10(4):e0125109. doi: 10.1371/journal.pone.0125109. eCollection 2015.
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.
血清素是一种由活化血小板释放的高度促炎分子，由色氨酸形成。犬尿氨酸的产生也需要色氨酸，这一过程由I型干扰素（IFN）调节的限速酶吲哚胺2,3-双加氧酶（IDO）介导。本研究的目的是调查自身免疫性疾病系统性红斑狼疮（SLE）患者的血清素水平、与临床表型的关联以及IDO在血清素合成调节中的可能作用。通过液相色谱和酶联免疫吸附测定法（ELISA）测量了SLE患者（n=148）和健康志愿者（n=79）血清和血浆中的血清素水平，并通过流式细胞术测量了血小板内的血清素水平。我们发现，与健康个体相比，SLE患者血清（p=0.01）和血小板（p<0.0001）中的血清素水平降低。通过内部报告基因检测确定具有持续I型IFN活性的SLE患者，其血清素水平降低（p=0.0008），同时IDO活性增加（p<0.0001），后者通过液相色谱测量的犬尿氨酸/色氨酸比值确定。此外，SLE血清以I型IFN依赖的方式诱导WISH细胞中IDO的表达（p=0.008）。血小板活化也导致血小板和血清中血清素水平的总体可用性降低（p<0.05）。血清素水平降低与存在抗双链DNA抗体和肾炎的严重SLE相关。总之，SLE患者血清素水平降低与包括肾炎在内的严重疾病表型有关，提示重要免疫病理过程的参与。此外，我们的数据表明，SLE血清中存在的I型IFN能够上调IDO表达，这可能导致血清素水平降低。
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