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Brain Advance Access originally published online on April 8, 2003
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Brain, Vol. 126, No. 6, 1371-1381, June 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg129

Gelatinase B/matrix metalloproteinase-9 cleaves interferon-ß and is a target for immunotherapy

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

Rega Institute for Medical Research, Laboratories of Molecular Immunology and Immunobiology, University of Leuven, Leuven, Belgium

Correspondence to: Professor Ghislain Opdenakker, MD, PhD, Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium E-mail: ghislain.opdenakker{at}rega.kuleuven.ac.be

Parenteral administration of interferon (IFN)-ß 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-ß, kills its activity, and hence counteracts this cytokine as an antiviral and immunotherapeutic agent. This proteolysis is more pronounced with IFN-ß-1b than with IFN-ß-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-ß by gelatinase B. These data provide a novel mechanism and rationale for the inhibition of gelatinase B in diseases in which IFN-ß has a beneficial effect. The combination of gelatinase B inhibitors with better and lower pharmacological formulations of IFN-ß may reduce the side-effects of treatment with IFN-ß, and is therefore proposed for multiple sclerosis therapy and the immunotherapy of viral infections.


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