Department of Psychological, Humanistic and Territorial Sciences, University "G. D'Annunzio", Chieti, Italy.
Department of Medicine and Science of Aging, University "G. D'Annunzio", Chieti, Italy.
Brain Behav Immun. 2014 Oct;41:251-60. doi: 10.1016/j.bbi.2014.04.008. Epub 2014 Apr 30.
Recent lines of research have boosted awareness of the immunological facets of schizophrenia. However, associations with protein tyrosine phosphatase regulators have never been reported. The aim of our study was to investigate the expression and promoter status methylation of phosphatase SHP-1, a key negative regulator of the inflammatory process, in Peripheral blood mononuclear cells (PBMCs) of Schizophrenic patients.
We enrolled fifty-four (28 men and 26 women) unmedicated first episode subjects (SC) who met DSM-IV and thirty-eight (22 men and 16 women) healthy controls (HC). The SC psychopathological status was assessed using the Positive and Negative Syndrome Scale. We evaluated SHP-1 expression by Quantitative Real-time PCR (qPCR) and Western blotting (WB) methods and promoter status methylation through PCR bisulfate. IKK/NFkB signaling was detected by WB, and medium and plasma levels of pro-inflammatory cytokines (IL-1β, IL-2, and TNF-α) by the ELISA method. SHP-1 was silenced by treating cells with specific siRNA.
We found a significantly lower level of SHP-1 gene expression in PBMCs from SC vs. HC, consistently with which the promoter region analyzed presented significant hypermethylation. Silencing of SHP-1 expression induced higher activation of IKK/NF-kB signaling and pro-inflammatory cytokine production in ex vivo PBMCs from both SC and HC. Linear regression among patients generated a model in which SHP-1 expression explained 30% of the clinical negative symptom variance (adjusted R(2)=0.30, ANOVA p<0.001).
Our findings are the first to suggest that impairment of SHP-1 expression is involved in the physiopathology of schizophrenia, opening fruitful new avenues for ameliorating treatment at least of negative symptoms.
最近的研究表明精神分裂症具有免疫学特征。然而，目前尚未有研究报道蛋白酪氨酸磷酸酶调节剂与精神分裂症之间的关联。本研究旨在探讨磷酸酶 SHP-1 的表达及其启动子甲基化状态在精神分裂症患者外周血单个核细胞（PBMC）中的变化。
我们招募了 54 名（28 名男性和 26 名女性）未经治疗的首发精神分裂症患者（SC）和 38 名（22 名男性和 16 名女性）健康对照者（HC）。SC 的精神病理状态采用阳性和阴性综合征量表（PANSS）进行评估。我们采用定量实时 PCR（qPCR）和 Western blot（WB）方法评估 SHP-1 的表达，通过 PCR 亚硫酸氢盐测序法评估启动子甲基化状态。通过 WB 检测 IKK/NFkB 信号，采用 ELISA 法检测促炎细胞因子（IL-1β、IL-2 和 TNF-α）的中、血浆水平。通过用特异性 siRNA 处理细胞来沉默 SHP-1。
我们发现 SC 患者的 PBMC 中 SHP-1 基因表达明显降低，相应的启动子区域分析显示明显的高甲基化。沉默 SHP-1 表达可诱导 SC 和 HC 患者的 PBMC 中 IKK/NF-kB 信号的更高激活和促炎细胞因子的产生。对患者进行线性回归，结果生成一个模型，其中 SHP-1 表达解释了 30%的临床阴性症状变异（调整后的 R²=0.30，ANOVA p<0.001）。
本研究首次表明 SHP-1 表达的损伤与精神分裂症的病理生理学有关，为改善至少阴性症状的治疗开辟了新的途径。
