Immune cells contain a specialised type of proteasome, i.e. the immunoproteasome, which is required for intracellular protein degradation. Immunoproteasomes are key regulators of immune cell differentiation, inflammatory activation and autoimmunity. Immunoproteasome function in peripheral immune cells might be altered by smoking and in chronic obstructive pulmonary disease (COPD), thereby affecting immune cell responses.

We analysed the expression and activity of proteasome complexes in peripheral blood mononuclear cells (PBMCs) isolated from healthy male young smokers as well as from patients with severe COPD and compared them with matching controls.

Proteasome expression was upregulated in COPD patients as assessed by quantitative reverse transcriptase-PCR and mass spectrometry-based proteomic analysis. Proteasome activity was quantified using activity-based probes and native gel analysis. We observed distinct activation of immunoproteasomes in the peripheral blood cells of young male smokers and severely ill COPD patients. Native gel analysis and linear regression modelling confirmed robust activation and elevated assembly of 20S proteasomes, which correlated significantly with reduced lung function parameters in COPD patients. The immunoproteasome was distinctly activated in COPD patients upon inflammatory cytokine stimulation of PBMCs in vitro. Inhibition of the immunoproteasome reduced pro-inflammatory cytokine expression in COPD-derived blood immune cells.

Given the crucial role of chronic inflammatory signalling and the emerging involvement of autoimmune responses in COPD, therapeutic targeting of the immunoproteasome might represent a novel therapeutic concept for COPD.

免疫细胞含有一种特殊类型的蛋白酶体，即免疫蛋白酶体，它是细胞内蛋白质降解所必需的。免疫蛋白酶体是免疫细胞分化、炎症激活和自身免疫的关键调节剂。吸烟和慢性阻塞性肺病 (COPD) 可能会改变外周免疫细胞中的免疫蛋白酶体功能，从而影响免疫细胞反应。

我们分析了从健康男性年轻吸烟者和重度 COPD 患者分离的外周血单个核细胞 (PBMC) 中蛋白酶体复合物的表达和活性，并将它们与匹配的对照进行比较。

通过定量逆转录酶-PCR 和基于质谱的蛋白质组学分析评估，在 COPD 患者中蛋白酶体表达上调。使用基于活性的探针和天然凝胶分析对蛋白酶体活性进行量化。我们观察到年轻男性吸烟者和重症 COPD 患者外周血细胞中免疫蛋白酶体的明显激活。天然凝胶分析和线性回归模型证实了 20S 蛋白酶体的强烈激活和升高的组装，这与 COPD 患者的肺功能参数降低显着相关。在体外PBMC 的炎性细胞因子刺激下，COPD 患者的免疫蛋白酶体明显激活. 抑制免疫蛋白酶体可降低 COPD 衍生的血液免疫细胞中促炎细胞因子的表达。

鉴于慢性炎症信号传导的关键作用和自身免疫反应在 COPD 中的新兴参与，免疫蛋白酶体的治疗靶向可能代表 COPD 的新治疗概念。