Gelatinase B functions as regulator and effector in leukocyte biology.
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.
Opdenakker
G
G
Laboratory of Molecular Immunology, Rega Institute, University of Leuven, Leuven, Belgium. ghislain.opdenakker@rega.kuleuven.ac.be
Van den Steen
P E
PE
Dubois
B
B
Nelissen
I
I
Van Coillie
E
E
Masure
S
S
Proost
P
P
Van Damme
J
J
D001327:Autoimmune Diseases / Q000201:enzymology; D018925:Chemokines / Q000502:physiology; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics; D016207:Cytokines / Q000502:physiology; D004789:Enzyme Activation; D004790:Enzyme Induction; D005109:Extracellular Matrix / Q000201:enzymology; D006801:Humans; D007962:Leukocytes / Q000166:cytology / Q000201:enzymology*; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D046911:Macromolecular Substances; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D009369:Neoplasms / Q000201:enzymology; D009504:Neutrophils / Q000166:cytology / Q000201:enzymology; D009928:Organ Specificity; D010641:Phenotype; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
D018925:Chemokines; D016207:Cytokines; D046911:Macromolecular Substances; D019715:Tissue Inhibitor of Metalloproteinase-1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9