Gelatinase B/matrix metalloproteinase-9 cleaves interferon-β and is a target for immunotherapy
Gelatinase B/matrix metalloproteinase-9 cleaves interferon-β and is a target for immunotherapy
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DOI：
10.1093/brain/awg129
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发表时间：
2003-06-01
期刊：
影响因子：
14.5
通讯作者：
Opdenakker, G
中科院分区：
文献类型：
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作者：
Nelissen, I;Martens, E;Opdenakker, G
干扰素（IFN）-β的肠胃外给药是目前批准的多发性硬化症的疗法之一。这种疾病的一个特征是明胶酶B（也称为基质金属蛋白酶（MMP）9）的产生增加。明胶酶B能够破坏血脑屏障，并将髓鞘碱性蛋白切割成免疫显性片段和致脑炎片段，从而在多发性硬化中发挥功能性作用并成为治疗靶点。在这里，我们证明了明胶酶B蛋白水解切割IFN-β，杀死其活性，从而抵消这种细胞因子作为抗病毒药和免疫剂。这种蛋白水解作用在IFN-β-1b中比在IFN-β-1a中更明显。此外，四环素米诺环素（其在实验性自身免疫性脑脊髓炎（多发性硬化症中急性炎症的体内模型）中具有已知的阻断作用）和其它MMP抑制剂防止明胶酶B对IFN-β的体外降解。这些数据为在IFN-β具有有益作用的疾病中抑制明胶酶B提供了新的机制和基本原理。明胶酶B抑制剂与更好和更低的IFN-β药理学制剂的组合可以减少用IFN-β治疗的副作用，因此被提议用于多发性硬化症治疗和病毒感染的免疫治疗。
Parenteral administration of interferon (IFN)-beta is one of the currently approved therapies for multiple sclerosis. One characteristic of this disease is the increased production of gelatinase B, also called matrix metalloproteinase (MMP) 9. Gelatinase B is capable of destroying the blood-brain barrier, and of cleaving myelin basic protein into immunodominant and encephalitogenic fragments, thus playing a functional role and being a therapeutic target in multiple sclerosis. Here we demonstrate that gelatinase B proteolytically cleaves IFN-beta, kills its activity, and hence counteracts this cytokine as an antiviral and immunotherapeutic agent. This proteolysis is more pronounced with IFN-beta-1b than with IFN-beta-1a. Furthermore, the tetracycline minocycline, which has a known blocking effect in experimental autoimmune encephalomyelitis, an in vivo model of acute inflammation in multiple sclerosis, and other MMP inhibitors prevent the in vitro degradation of IFN-beta by gelatinase B. These data provide a novel mechanism and rationale for the inhibition of gelatinase B in diseases in which IFN-beta has a beneficial effect. The combination of gelatinase B inhibitors with better and lower pharmacological formulations of IFN-beta may reduce the side-effects of treatment with IFN-beta, and is therefore proposed for multiple sclerosis therapy and the immunotherapy of viral infections.