Khan Abid, Southworth Thomas, Worsley Sally, Sriskantharajah Srividya, Amour Augustin, Hessel Edith M, Singh Dave
The University of Manchester, Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, The University of Manchester, Manchester, UK.
The University of Manchester, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, Manchester, UK.
Clin Exp Pharmacol Physiol. 2017 Sep;44(9):932-940. doi: 10.1111/1440-1681.12784.
Lymphocyte numbers are increased in the lungs of chronic obstructive pulmonary disease (COPD) patients. Phosphatidylinositol-3-kinase delta (PI3Kδ) is involved in lymphocyte activation. We investigated the effect of PI3Kδ inhibition on cytokine release from COPD lymphocytes. We also evaluated phosphorylated ribosomal S6 protein (rS6) as a potential biomarker of PI3Kδ activation. Peripheral blood mononuclear cells (PBMCs) and bronchoalveolar lavage (BAL) cells isolated from healthy never smokers (HNS), smokers (S) and COPD patients were stimulated to induce a T cell receptor response. The effects of a PI3Kδ specific inhibitor (GSK045) on cytokine release and rS6 phosphorylation were measured by Luminex and flow cytometry respectively. The effects of GSK045 on cytokine production from PHA stimulated chopped lung samples were investigated. GSK045 reduced cytokine release from PBMCs, BAL cells and chopped lung. Inhibition was greatest in the chopped lung model, with approximately 80% inhibition of interferon (IFN) γ, interleukin (IL)-2, IL-17 and IL-10. PI3Kδ inhibition suppressed rS6 phosphorylation in unstimulated airway T-lymphocytes by up to 60%. Inhibition of PI3Kδ suppressed T cell cytokine production in COPD patients. rS6 phosphorylation shows potential as a biomarker to assess PI3Kδ activity.
慢性阻塞性肺疾病（COPD）患者肺部的淋巴细胞数量增加。磷脂酰肌醇-3-激酶δ（PI3Kδ）参与淋巴细胞活化。我们研究了PI3Kδ抑制对COPD淋巴细胞细胞因子释放的影响。我们还评估了磷酸化核糖体S6蛋白（rS6）作为PI3Kδ活化的潜在生物标志物。从健康非吸烟者（HNS）、吸烟者（S）和COPD患者中分离出外周血单核细胞（PBMC）和支气管肺泡灌洗（BAL）细胞，刺激诱导T细胞受体反应。分别通过Luminex和流式细胞术检测PI3Kδ特异性抑制剂（GSK045）对细胞因子释放和rS6磷酸化的影响。研究了GSK045对PHA刺激的切碎肺样本中细胞因子产生的影响。GSK045减少了PBMC、BAL细胞和切碎肺中的细胞因子释放。在切碎肺模型中抑制作用最大，干扰素（IFN）γ、白细胞介素（IL）-2、IL-17和IL-10的抑制率约为80%。PI3Kδ抑制可使未刺激的气道T淋巴细胞中的rS6磷酸化抑制高达60%。抑制PI3Kδ可抑制COPD患者的T细胞细胞因子产生。rS6磷酸化显示出作为评估PI3Kδ活性生物标志物的潜力。
