Schwieler Lilly, Larsson Markus K, Skogh Elisabeth, Kegel Magdalena E, Orhan Funda, Abdelmoaty Sally, Finn Anja, Bhat Maria, Samuelsson Martin, Lundberg Kristina, Dahl Marja-Liisa, Sellgren Carl, Schuppe-Koistinen Ina, Svensson Camilla, Erhardt Sophie, Engberg Göran
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical and Experimental Medicine, Section of Psychiatry, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
J Psychiatry Neurosci. 2015 Mar;40(2):126-33. doi: 10.1503/jpn.140126.
Accumulating evidence indicates that schizophrenia is associated with brain immune activation. While a number of reports suggest increased cytokine levels in patients with schizophrenia, many of these studies have been limited by their focus on peripheral cytokines or confounded by various antipsychotic treatments. Here, well-characterized patients with schizophrenia, all receiving olanzapine treatment, and healthy volunteers were analyzed with regard to cerebrospinal fluid (CSF) levels of cytokines. We correlated the CSF cytokine levels to previously analyzed metabolites of the kynurenine (KYN) pathway.
We analyzed the CSF from patients and controls using electrochemiluminescence detection with regard to cytokines. Cell culture media from human cortical astrocytes were analyzed for KYN and kynurenic acid (KYNA) using high-pressure liquid chromatography or liquid chromatography/mass spectrometry.
We included 23 patients and 37 controls in our study. Patients with schizophrenia had increased CSF levels of interleukin (IL)-6 compared with healthy volunteers. In patients, we also observed a positive correlation between IL-6 and the tryptophan:KYNA ratio, indicating that IL-6 activates the KYN pathway. In line with this, application of IL-6 to cultured human astrocytes increased cell medium concentration of KYNA.
The CSF samples had been frozen and thawed twice before analysis of cytokines. Median age differed between patients and controls. When appropriate, all present analyses were adjusted for age.
We have shown that IL-6, KYN and KYNA are elevated in patients with chronic schizophrenia, strengthening the idea of brain immune activation in patients with this disease. Our concurrent cell culture and clinical findings suggest that IL-6 induces the KYN pathway, leading to increased production of the N-methyl-D-aspartate receptor antagonist KYNA in patients with schizophrenia.
越来越多的证据表明，精神分裂症与大脑免疫激活有关。虽然许多报告表明精神分裂症患者体内细胞因子水平升高，但这些研究大多局限于外周细胞因子，或因各种抗精神病药物治疗而混淆。在此，我们对特征明确、均接受奥氮平治疗的精神分裂症患者和健康志愿者的脑脊液（CSF）细胞因子水平进行了分析。我们将脑脊液细胞因子水平与先前分析的犬尿氨酸（KYN）途径代谢产物进行了关联。
我们使用电化学发光检测法分析患者和对照组脑脊液中的细胞因子。使用高压液相色谱或液相色谱/质谱法分析人皮质星形胶质细胞的细胞培养基中的犬尿氨酸（KYN）和犬尿喹啉酸（KYNA）。
我们的研究纳入了23名患者和37名对照。与健康志愿者相比，精神分裂症患者脑脊液中白细胞介素（IL）-6水平升高。在患者中，我们还观察到IL-6与色氨酸：KYNA比值之间呈正相关，表明IL-6激活了KYN途径。与此一致的是，将IL-6应用于培养的人星形胶质细胞会增加细胞培养基中KYNA的浓度。
在分析细胞因子之前，脑脊液样本已冷冻和解冻两次。患者和对照组的年龄中位数不同。在适当的时候，所有当前分析均针对年龄进行了调整。
我们已经表明，慢性精神分裂症患者体内IL-6、KYN和KYNA水平升高，强化了该疾病患者大脑免疫激活的观点。我们同时进行的细胞培养和临床研究结果表明，IL-6诱导KYN途径，导致精神分裂症患者体内N-甲基-D-天冬氨酸受体拮抗剂KYNA的产生增加。
