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Gelatinase B functions as regulator and effector in leukocyte biology
Author(s) -
Opdenakker Ghislain,
Van den Steen Philippe E.,
Dubois Bénédicte,
Nelissen Inge,
Van Coillie Els,
Masure Stefan,
Proost Paul,
Van Damme Jo
Publication year - 2001
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.69.6.851
Subject(s) - gelatinase , biology , proteases , matrix metalloproteinase , gelatinase a , fibroblast activation protein, alpha , microbiology and biotechnology , extracellular matrix , enzyme , biochemistry , genetics , cancer
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 α 2 ‐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‐1β into active IL‐1β. 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 aminoterminus into a tenfold more potent chemokine, resulting in an important positive feedback loop for neutrophil activation and chemotaxis. The CXC chemokines GRO‐α, CTAP‐III, and PF‐4 are degraded by gelatinase B, whereas the CC chemokines MCP‐2 and RANTES are not cleaved.