Gelatinase B Functions as Regulator and Effector in Leukocyte Biology

J Leukoc Biol. 2001 Jun;69(6):851-9.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Autoimmune Diseases / enzymology
  • Chemokines / physiology
  • Chromosomes, Human, Pair 20 / genetics
  • Cytokines / physiology
  • Enzyme Activation
  • Enzyme Induction
  • Extracellular Matrix / enzymology
  • Humans
  • Leukocytes / cytology
  • Leukocytes / enzymology*
  • Leukocytes, Mononuclear / enzymology
  • Macromolecular Substances
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / chemistry
  • Matrix Metalloproteinase 9 / deficiency
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / immunology
  • Matrix Metalloproteinase 9 / physiology*
  • Neoplasms / enzymology
  • Neutrophils / cytology
  • Neutrophils / enzymology
  • Organ Specificity
  • Phenotype
  • Protein Processing, Post-Translational
  • Protein Structure, Tertiary
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism

Substances

  • Chemokines
  • Cytokines
  • Macromolecular Substances
  • Tissue Inhibitor of Metalloproteinase-1
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9