Journal Article

Gelatinase B/matrix metalloproteinase‐9 cleaves interferon‐β and is a target for immunotherapy

Inge Nelissen, Erik Martens, Philippe E. Van Den Steen, Paul Proost, Isabelle Ronsse and Ghislain Opdenakker

in Brain

Published on behalf of The Guarantors of Brain

Volume 126, issue 6, pages 1371-1381
Published in print June 2003 | ISSN: 0006-8950
Published online June 2003 | e-ISSN: 1460-2156 | DOI: http://dx.doi.org/10.1093/brain/awg129
Gelatinase B/matrix metalloproteinase‐9 cleaves interferon‐β and is a target for immunotherapy

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Parenteral administration of interferon (IFN)‐β is one of the currently approved therapies for multiple sclerosis. One characteristic of this disease is the increased production of gelatinase B, also called matrix metalloproteinase (MMP) 9. Gelatinase B is capable of destroying the blood–brain barrier, and of cleaving myelin basic protein into immunodominant and encephalitogenic fragments, thus playing a functional role and being a therapeutic target in multiple sclerosis. Here we demonstrate that gelatinase B proteolytically cleaves IFN‐β, kills its activity, and hence counteracts this cytokine as an antiviral and immunotherapeutic agent. This proteolysis is more pronounced with IFN‐β‐1b than with IFN‐β‐1a. Furthermore, the tetracycline minocycline, which has a known blocking effect in experimental autoimmune encephalomyelitis, an in vivo model of acute inflammation in multiple sclerosis, and other MMP inhibitors prevent the in vitro degradation of IFN‐β by gelatinase B. These data provide a novel mechanism and rationale for the inhibition of gelatinase B in diseases in which IFN‐β has a beneficial effect. The combination of gelatinase B inhibitors with better and lower pharmacological formulations of IFN‐β may reduce the side‐effects of treatment with IFN‐β, and is therefore proposed for multiple sclerosis therapy and the immunotherapy of viral infections.

Keywords: Keywords: gelatinase B; interferon; multiple sclerosis; inflammation; viral infection; Abbreviations: CHO = Chinese hamster ovary; CPE = cytopathogenic effect; EAE = experimental autoimmune encephalomyelitis; EDTA = ethylenediaminetetraacetic acid; HSA = human serum albumin; IFN = interferon; MMP = matrix metalloproteinase; SDS–PAGE = sodium dodecyl sulphate–polyacrylamide gel electrophoresis

Journal Article.  7572 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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