Gelatinase B functions as regulator and effector in leukocyte biology

Matrix metalloproteinases (MMPs) form a family of enzymes with major action s 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 a t various levels: transcription of the gene by cytokines and cellular inter actions; activation of the pro-enzyme by a cascade of enzymes comprising se rine proteases and other MMPs; and regulation by specific tissue inhibitors of MMPs (TIMPs) or by unspecific inhibitors, such as alpha (2)-macroglobul in. Thus, remodeling ECM is the result of the local protease load, i.e., th e net balance between enzymes and inhibitors. Glycosylation has a limited e ffect oil the net activity of gelatinase B, and in contrast to the all-or-n one 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 gela tinase B from neutrophils, induced by various types of chemotactic factors, is another level of control of activity, Neutrophils are first-line defens e leukocytes and no not produce gelatinase A or TIMP, Thus, neutrophils con trast sharply with mononuclear leukocytes, which produce gelatinase A const itutively, synthesize gelatinase B de novo after adequate triggering, and o verproduce TIMP-1, Gelatinase B is also endowed with functions other than c leaving the ECM, It has beets shown to generate autoimmune neo-epitopes and to activate pro-IL-1 beta into active IL-1 beta. Gelatinase B ablation in the mouse leads to altered bone remodeling and subfertility, results in res istance to several induced inflammatory or autoimmune pathologies, and indi cates that the enzyme plays a crucial role in development and angiogenesis. The major human neutrophil chemoattractant, IL-8, stimulates fast degranul ation of gelatinase B from neutrophils. Gelatinase B is also found to funct ion as a regulator of neutrophil biology and to truncate IL-8 at the aminot erminus into a tenfold more potent chemokine, resulting in an important pos itive feedback loop for neutrophil activation and chemotaxis, The CXC chemo kines GRO-alpha, CTAP-III, and PF-4 are degraded by gelatinase B, whereas t he CC chemokines MCP-2 and RANTES are not cleaved.