Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
J Cell Mol Med. 2011 Nov;15(11):2421-9. doi: 10.1111/j.1582-4934.2010.01229.x.
Cathepsins are involved in a variety of physiological processes including antigen processing and presentation and extracellular matrix degradation. In the present study, we evaluated whether expression levels of cathepsins S and B and their inhibitors cystatins B and C are affected by multiple sclerosis (MS) disease state (relapse and remission) and therapies (interferon-β [IFN-β] and the glucocorticoid [GC] methylprednisolone), and whether they are associated with the IFN-β response phenotype. Real-time PCR was employed to compare RNA expression levels in peripheral blood leucocytes (PBLs) and ELISA to determine serum protein levels of MS patients and matched healthy individuals. Cathepsin S RNA was higher in MS patients in the relapse state compared to controls (by 74%, P = 3 × 10(-5), n = 30 versus n = 18) with a similar increase observed in serum (66%, P = 0.002, n = 18 versus n = 20). GC treatment reduced cathepsin S levels in PBL RNA (by 44%, P = 6 × 10(-6), n = 27) and serum proteins (by 27%, P = 1 × 10(-5), n = 26), reduced the serum protein levels of pro-cathepsin B (by 8%, P = 0.0007, n = 23), and in parallel increased the serum levels of their inhibitor cystatin C (by 82%, P = 8 × 10(-6), n = 26). IFN-β therapy significantly elevated the RNA levels (n = 16) of cathepsin B (by 16%, P = 0.03), cystatin B (44%, P = 0.004) and cystatin C (48%, P = 0.011). In the serum, only cathepsin S levels were reduced by IFN-β (16%, P = 0.006, n = 25). Interestingly, pre-treatment serum cathepsin S/cystatin C ratio was higher in 'good responders' to IFN-β therapy compared to patients without a good response (by 94%, P = 0.003). These results suggest that cathepsin S and cystatin C may contribute to disease activity in MS, specifically in a subgroup of patients that are responsive to IFN-β therapy, and that these proteins should be further evaluated as biomarkers in MS.
组织蛋白酶参与多种生理过程，包括抗原加工和呈递以及细胞外基质降解。在本研究中，我们评估了组织蛋白酶 S 和 B 及其抑制剂胱抑素 B 和 C 的表达水平是否受多发性硬化症 (MS) 疾病状态（复发和缓解）和治疗（干扰素-β [IFN-β] 和糖皮质激素 [GC] 甲基强的松龙）的影响，以及它们是否与 IFN-β 反应表型相关。采用实时 PCR 比较外周血白细胞 (PBL) 中的 RNA 表达水平，ELISA 测定 MS 患者和匹配健康个体的血清蛋白水平。与对照组相比，处于复发状态的 MS 患者的组织蛋白酶 S RNA 更高（增加 74%，P = 3×10(-5)，n = 30 与 n = 18），血清中也观察到类似的增加（增加 66%，P = 0.002，n = 18 与 n = 20）。GC 治疗降低了 PBL RNA 中的组织蛋白酶 S 水平（降低 44%，P = 6×10(-6)，n = 27）和血清蛋白水平（降低 27%，P = 1×10(-5)，n = 26），降低了前组织蛋白酶 B 的血清蛋白水平（降低 8%，P = 0.0007，n = 23），并平行增加了其抑制剂胱抑素 C 的血清水平（增加 82%，P = 8×10(-6)，n = 26）。IFN-β 治疗显著提高了组织蛋白酶 B（增加 16%，P = 0.03）、胱抑素 B（增加 44%，P = 0.004）和胱抑素 C（增加 48%，P = 0.011）的 RNA 水平（n = 16）。在血清中，只有 IFN-β 降低了组织蛋白酶 S 水平（降低 16%，P = 0.006，n = 25）。有趣的是，与无良好反应的患者相比，“良好反应者”的 IFN-β 治疗前血清组织蛋白酶 S/胱抑素 C 比值更高（增加 94%，P = 0.003）。这些结果表明，组织蛋白酶 S 和胱抑素 C 可能有助于 MS 的疾病活动，特别是在对 IFN-β 治疗有反应的患者亚群中，这些蛋白应作为 MS 的生物标志物进一步评估。
