Gelatinase B/matrix metalloproteinase-9 provokes cataract by cleaving lens betaB1 crystallin

Parenteral administration of interferon (IFN)-b is one of the currently approved therapies for multiple scler-osis. One characteristic of this disease is the increased production of gelatinase B, also called matrix metallo-proteinase (MMP) 9. Gelatinase B is capable of destroy-ing the blood±brain barrier, and of cleaving myelin basic protein into immunodominant and encephalito-genic fragments, thus playing a functional role and being a therapeutic target in multiple sclerosis. Here we demonstrate that gelatinase B proteolytically cleaves IFN-b, kills its activity, and hence counteracts this cyto-kine as an antiviral and immunotherapeutic agent. This proteolysis is more pronounced with IFN-b-1b than with IFN-b-1a. Furthermore, the tetracycline mino-cycline, which has a known blocking effect in experi-mental autoimmune encephalomyelitis, an in vivo model of acute in¯ammation in multiple sclerosis, and other MMP inhibitors prevent the in vitro degradation of IFN-b by gelatinase B. These data provide a novel mechanism and rationale for the inhibition of gelatinase B in diseases in which IFN-b has a bene®cial effect. The combination of gelatinase B inhibitors with better and lower pharmacological formulations of IFN-b may reduce the side-effects of treatment with IFN-b, and is therefore proposed for multiple sclerosis therapy and the immunotherapy of viral infections. Keywords: gelatinase B; interferon; multiple sclerosis; in¯ammation; 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 electrophoresi