Gelatinase B/matrix metalloproteinase-9 cleaves interferon-beta and is a target for immunotherapy.
Parenteral administration of interferon (IFN)-beta 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-beta, kills its activity, and hence counteracts this cytokine as an antiviral and immunotherapeutic agent. This proteolysis is more pronounced with IFN-beta-1b than with IFN-beta-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-beta by gelatinase B. These data provide a novel mechanism and rationale for the inhibition of gelatinase B in diseases in which IFN-beta has a beneficial effect. The combination of gelatinase B inhibitors with better and lower pharmacological formulations of IFN-beta may reduce the side-effects of treatment with IFN-beta, and is therefore proposed for multiple sclerosis therapy and the immunotherapy of viral infections.
Nelissen
Inge
I
Rega Institute for Medical Research, Laboratory of Molecular Immunology, University of Leuven, Leuven, Belgium.
Martens
Erik
E
Van den Steen
Philippe E
PE
Proost
Paul
P
Ronsse
Isabelle
I
Opdenakker
Ghislain
G
D000998:Antiviral Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007370:Interferon Type I / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000494:pharmacology; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry*; D009103:Multiple Sclerosis / Q000628:therapy; D011487:Protein Conformation; D011994:Recombinant Proteins
D000998:Antiviral Agents; D007370:Interferon Type I; D011994:Recombinant Proteins; D016899:Interferon-beta; D020780:Matrix Metalloproteinase 9