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

Abstract

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.