Different effects of simvastatin and interferon beta on the proteolytic activity of matrix metalloproteinases

Background: Interferon beta and statins are known to exert immunomodulatory actions by inhibiting gene transcription and translation of various proinflammatory molecules. Although interferon beta represents a mainstay in therapy for multiple sclerosis (MS), statins are considered a potential new approach in treating MS. Objective: To investigate the effect of interferon beta and statins on the posttranslational activity of matrix metalloproteinases (MMPs) released from mononuclear cells in vitro that were obtained from patients with MS and healthy donors. Design: Blood samples from 10 patients with a relapsing-remitting course of MS and 5 matched healthy individuals were studied. Peripheral blood mononuclear cells were isolated and stimulated with an antibody to CD3, phytohemagglutinin, or medium alone as a negative control. Proteolytic activity was investigated in the supernatants by means of sodium dodecyl sulfate-polyacrylamide gel electrophoresis zymography in which gels were incubated with interferon beta or simvastatin during development. Zones of gelatin digestion were visualized and quantified. Results: Incubation with interferon beta resulted in an inhibition of the gelatinolytic activity of MMP-9 and MMP-2. In contrast, simvastatin enhanced the proteolytic capacity of MMP-2 and MMP-9, with a statistically significant increase of MMP-2 activity when compared with findings in controls. There were no differences in the enzymatic response between patients with MS and healthy individuals. Conclusions: Interferon beta exhibits inhibitory effects at the posttranslational level of MMP activity, whereas simvastatin augments the proteolytic activity of MMP-2 and MMP-9, suggesting that statins exert anti-inflammatory and proinflammatory effects. This dual mechanism of action should be considered, given the recent interest in developing these drugs for treatment of MS.