Interferon beta-1b inhibits gelatinase secretion and in vitro migration of human T cells: A possible mechanism for treatment efficacy in multiple sclerosis
Interferon beta-1b inhibits gelatinase secretion and in vitro migration of human T cells: A possible mechanism for treatment efficacy in multiple sclerosis
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DOI：
10.1002/ana.410400606
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发表时间：
1996-12-01
影响因子：
11.2
通讯作者：
Hauser, SL
中科院分区：
文献类型：
--
作者：
Leppert, D;Waubant, E;Hauser, SL
用干扰素β-lb治疗在脱髓鞘疾病多发性硬化中具有显著的临床益处，但在该疾病中的作用机制仍在很大程度上未知。明胶酶A（基质金属蛋白酶-2，72-kd明胶酶）和B（基质金属蛋白酶-9，92-kd明胶酶）是能够酶促消化内皮下基底膜成分的基质金属蛋白酶。在人类T细胞中，白细胞介素-2诱导明胶酶分泌，并增强明胶酶依赖性迁移穿过人工基底膜样层在体外。用干扰素β-lb预处理T细胞48小时减少了白细胞介素-2诱导的明胶酶产生和分泌，如通过酶谱法测定的。在平行的明胶酶分泌下调，预处理干扰素β-1b抑制T细胞迁移通过基底膜在体外高达90%，但只有一个轻微的影响细胞运动本身。对于明胶酶分泌和T细胞迁移，通过暴露于干扰素β-lb介导的抑制作用是剂量依赖性的。干扰素激活细胞分选仪分析还显示，干扰素β-1b下调白细胞介素-2受体a链，并将白细胞介素-2与细胞表面的亲和力降低30%，这可能代表了干扰素β-1b观察到的作用的另一种机制。干扰素β-Ib对明胶酶表达和迁移的显著作用提高了其在多发性硬化症中的有益作用是由于干扰活化的T细胞穿过基底膜并迁移到中枢神经系统的能力的可能性。
Treatment with interferon beta-lb has substantial clinical benefit in the demyelinating disease multiple sclerosis, yet the mechanism of action in the disease remains largely unknown. Gelatinase A (matrix metalloproteinase-2, 72-kd gelatinase) and B (matrix metalloproteinase-9, 92-kd gelatinase) are matrix metalloproteinases capable of enzymatic digestion of subendothelial basement membrane constituents. In human T cells, interleukin-2 induces gelatinase secretion and enhances gelatinase-dependent migration across an artificial basement membrane-like layer in vitro. Pretreatment of T cells with interferon beta-lb for 48 hours decreased interleukin-2-induced gelatinase production and secretion as determined by zymography. In parallel to the downregulation of gelatinase secretion, pretreatment with interferon beta-1b inhibited T-cell migration across the basement membrane in vitro by up to 90%, but had only a minor impact on cell locomotion per se. For both gelatinase secretion and T-cell migration, the inhibitory effect mediated by exposure to interferon beta-lb was dose dependent. Fluorescence-activated cell sorter analysis also showed that interferon beta-1b downregulates the interleukin-2 receptor a-chain and lowered the affinity of interleukin-2 to the cell surface by 30%, which may represent an additional mechanism for the observed effects of interferon beta-lb. The dramatic effects of interferon beta-lb on gelatinase expression and migration raise the possibility that its beneficial effects in multiple sclerosis map result from interference with the capacity of activated T cells to traverse the basement membrane and migrate to the central nervous system.