Opdenakker G, Van den Steen P E, Dubois B, Nelissen I, Van Coillie E, Masure S, Proost P, Van Damme J
Laboratory of Molecular Immunology, Rega Institute, University of Leuven, Leuven, Belgium.
J Leukoc Biol. 2001 Jun;69(6):851-9.
Matrix metalloproteinases (MMPs) form a family of enzymes with major actions in the remodeling of extracellular matrix (ECM) components. Gelatinase B (MMP-9) is the most complex family member in terms of domain structure and regulation of its activity. Gelatinase B activity is under strict control at various levels: transcription of the gene by cytokines and cellular interactions; activation of the pro-enzyme by a cascade of enzymes comprising serine proteases and other MMPs; and regulation by specific tissue inhibitors of MMPs (TIMPs) or by unspecific inhibitors, such as alpha2-macroglobulin. Thus, remodeling ECM is the result of the local protease load, i.e., the net balance between enzymes and inhibitors. Glycosylation has a limited effect on the net activity of gelatinase B, and in contrast to the all-or-none effect of enzyme activation or inhibition, it results in a higher-level, fine-tuning effect on the ECM catalysis by proteases in mammalian species. Fast degranulation of considerable amounts of intracellularly stored gelatinase B from neutrophils, induced by various types of chemotactic factors, is another level of control of activity. Neutrophils are first-line defense leukocytes and do not produce gelatinase A or TIMP. Thus, neutrophils contrast sharply with mononuclear leukocytes, which produce gelatinase A constitutively, synthesize gelatinase B de novo after adequate triggering, and overproduce TIMP-1. Gelatinase B is also endowed with functions other than cleaving the ECM. It has been shown to generate autoimmune neo-epitopes and to activate pro-IL-1beta into active IL-1beta. Gelatinase B ablation in the mouse leads to altered bone remodeling and subfertility, results in resistance to several induced inflammatory or autoimmune pathologies, and indicates that the enzyme plays a crucial role in development and angiogenesis. The major human neutrophil chemoattractant, IL-8, stimulates fast degranulation of gelatinase B from neutrophils. Gelatinase B is also found to function as a regulator of neutrophil biology and to truncate IL-8 at the amino terminus into a tenfold more potent chemokine, resulting in an important positive feedback loop for neutrophil activation and chemotaxis. The CXC chemokines GRO-alpha, CTAP-III, and PF-4 are degraded by gelatinase B, whereas the CC chemokines MCP-2 and RANTES are not cleaved.
基质金属蛋白酶（MMPs）构成了一类酶家族，在细胞外基质（ECM）成分的重塑中起主要作用。就结构域结构及其活性调节而言，明胶酶B（MMP-9）是最复杂的家族成员。明胶酶B的活性在各个水平上都受到严格控制：细胞因子和细胞间相互作用对基因转录的调控；由包括丝氨酸蛋白酶和其他MMPs的一系列酶对酶原的激活；以及MMPs特异性组织抑制剂（TIMPs）或非特异性抑制剂（如α2-巨球蛋白）的调节。因此，ECM重塑是局部蛋白酶负荷的结果，即酶与抑制剂之间的净平衡。糖基化对明胶酶B的净活性影响有限，与酶激活或抑制的全或无效应不同，它对哺乳动物物种中蛋白酶对ECM的催化作用产生更高水平的微调效应。由各种趋化因子诱导的嗜中性粒细胞中大量细胞内储存的明胶酶B的快速脱颗粒是活性控制的另一个层面。嗜中性粒细胞是一线防御白细胞，不产生明胶酶A或TIMP。因此，嗜中性粒细胞与单核白细胞形成鲜明对比，单核白细胞组成性产生明胶酶A，在充分触发后从头合成明胶酶B，并过量产生TIMP-1。明胶酶B还具有除切割ECM之外的其他功能。已证明它能产生自身免疫新表位，并将前白细胞介素-1β激活为活性白细胞介素-1β。小鼠体内明胶酶B的缺失会导致骨重塑改变和生育力下降，对几种诱导性炎症或自身免疫性疾病产生抗性，并表明该酶在发育和血管生成中起关键作用。主要的人类嗜中性粒细胞趋化因子白细胞介素-8刺激嗜中性粒细胞中明胶酶B的快速脱颗粒。还发现明胶酶B作为嗜中性粒细胞生物学的调节剂，将白细胞介素-8在氨基末端截短为效力高十倍的趋化因子，从而形成嗜中性粒细胞激活和趋化的重要正反馈回路。CXC趋化因子GRO-α、CTAP-III和PF-4被明胶酶B降解，而CC趋化因子MCP-2和RANTES不被切割。
