Trends in Immunology
Volume 22, Issue 10, 1 October 2001, Pages 571-579
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Review
Gelatinase B: a tuner and amplifier of immune functions

https://doi.org/10.1016/S1471-4906(01)02023-3Get rights and content

Abstract

Gelatinase B (matrix metalloproteinase-9) is a secreted multidomain enzyme that is important for the remodeling of the extracellular matrix and the migration of normal and tumor cells. It cleaves denatured collagens (gelatins) and type IV collagen, which is present in basement membranes. In the immune system, this cleavage helps lymphocytes and other leukocytes to enter and leave the blood and lymph circulations. Gelatinase B also cleaves myelin basic protein and type II gelatins, and this clipping leads to remnant epitopes that generate autoimmunity, the so-called REGA model of autoimmunity. Recently, gelatinase B has been found to process cytokines and chemokines, resulting in skewed immune functions. Therefore, gelatinase B, often considered as a pure effector molecule, acts as a switch and catalyst in both innate and specific immunity, and constitutes a prototypic example of the regulation of immune functions by proteolysis.

Section snippets

Comparison of gelatinases A and B

Gelatinases are rather complex MMPs. Similar to the collagenases, stromelysins and membrane-type MMPs (MT-MMPs), gelatinases contain a prodomain that imposes latency by a cysteine-switch mechanism 19, 20. This prodomain is followed by an active enzyme domain and a zinc-binding domain that form the catalytic site. The hemopexin domain plays a role in substrate specificity and binding to TIMPs (Ref. 1). In addition, gelatinases have an additional fibronectin-like domain. This consists of three

Regulation of the production of gelatinase B by immune cells

Gelatinase B was first identified in neutrophils 31, and later, in monocytes and/or macrophages 32; the electrophoretically pure natural pro-form of human gelatinase B was obtained from neutrophils. Neutrophils do not produce gelatinase A or TIMP-1 and consequently, do not form complexes of gelatinase B with TIMP-1 (33, 34). APCs, such as monocytes, fibroblasts, dendritic cells (DCs) and lymphocytes, also produce gelatinases. In general, all of these types of cell secrete gelatinase A

Role in immunopathology

Collagens are denatured in vivo into gelatins by means of a single cleavage by collagenases. The major role of gelatinase B in vitro (i.e. gelatinolysis) has not been demonstrated in vivo yet, though it is now possible to study, for instance, remodeling of the ECM, degradation of type IV collagen and destruction of the basement membrane in gelatinase B knockout mice. Meanwhile, other types of experiment have documented the importance of gelatinase B in the homeostasis of mature and immature

Pharmacological inhibition

In general, pro-inflammatory, T helper 1 (Th1)-type cytokines and chemokines, such as IL-1, IL-2, TNF-α and IL-8, induce the cellular production of gelatinase B, whereas anti-inflammatory, Th2-type cytokines, such as IL-4, IFN-β, IL-6 and IL-10, negatively regulate the protease balance by limiting the production of gelatinase B and enhancing the production of TIMP-1. In many diseases with excessive inflammation, it might be desirable to inhibit the production or action of gelatinase B

Conclusions and perspectives

Recently, gelatinase B has been upgraded from an effector molecule of innate immunity to an important regulator of the adaptive immune system and a target for inhibition in various diseases. It regulates the activities of cytokines and chemokines and plays a fundamental role in autoimmune diseases. Many aspects of the immunobiology of gelatinase B remain elusive. What are the pathways of regulation of gelatinase B after cell adhesion and formation of the immune synapse? How is gelatinase B

Acknowledgements

This work was supported by the Geconcerteerde Onderzoeks Acties, the Fund for Scientific Research (FWO-Vlaanderen), the Charcot Foundation, the Belgian Federation against Cancer and the Cancer Research Foundation of Fortis AB, Belgium. P.E.VDS is a research assistant of the FWO-Vlaanderen. In an attempt to bridge the literature of the past decade, original citations are complemented with novel conceptual references and review articles. Because of space limitations, the reference list is not

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