Gelatinase B functions as regulator and effector in leukocyte biology

By G. Opdenakker, P. E. Van den Steen, B. Dubois, I. Nelissen, E. van Coillie, S. Masure, P. Proost, J. Van Damme. Journal of Leukocyte Biology, 2001

596 citations recorded by the source corpus.

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 α2‐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.

Subfields: Biotechnology, Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/50968deef962e8797d31fae30f537bd3992ad5b8

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In Cancer Research

1. P. E. Van den Steen
2. G. Opdenakker
3. J. Vandooren
4. T. Mabuchi
5. G. D. del Zoppo

In Molecular Biology

1. J. Vandooren
2. T. Mabuchi
3. G. Opdenakker
4. P. E. Van den Steen
5. G. D. del Zoppo

Citations in the corpus

• Arginase I–Producing Myeloid-Derived Suppressor Cells in Renal Cell Carcinoma Are a Subpopulation of Activated Granulocytes (2009, unknown): “In addition, the levels of gelatinase A, which is not produced by PMN (19), were similar in the plasma from RCC patients and controls (Supplementary Fig.”
• Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): The next decade (2013, methodology): “In particular, the O-glycosylated domain was first represented as a bar, as its shape was hypothesized to be highly elongated due to steric effects of the O-linked sugars (Opdenakker et al., 2001b).”
• Biochemistry and Molecular Biology of Gelatinase B or Matrix Metalloproteinase-9 (MMP-9) (2002, background): “In comparison with the other MMPs, gelatinase B is structurally one of the most complex members of the family (Cuzner and Opdenakker, 1999; Opdenakker et al., 2001a; Opdenakker et al., 2001b; Van den Steen et al., 2001).”
• Cerebral Microvessel Responses to Focal Ischemia (2003, background): “…thrombin (Okada et al., 1994a; Aschner et al., 1997), active matrix metalloproteinases (MMPs) (Heo et al., 1999), proteases released by activated leukocytes (Hasty et al., 1990; Garcia et al., 1994; Armao et al., 1997; Opdenakker et al., 2001), and other protease activities (Hosomi et al., 2001).”
• Matrix metalloproteinases: Contribution to pathogenesis, diagnosis and treatment of periodontal inflammation (2006, background): “In this regard, IL-8 expressed by periodontitis-affected gingival sulcular epithelial cells can provoke the release of MMP-8 and -9 by recruited neutrophils and is also a potential target of the released MMPs (59,64,80,85,86).”