Interferon-beta-1b decreased matrix metalloproteinase-9 serum levels in primary progressive multiple sclerosis

Abstract

Recent reports have shown that matrix-metalloproteinases (MMPs) facilitate T-cell migration into the CNS and play a role in disruption of the blood-brain-barrier and myelin breakdown. An increase of MMP-9 serum levels predicts disease activity in relapsing remitting multiple sclerosis (RRMS). Interferon-beta (IFN-beta), which is an established treatment for RRMS, inhibits T-cell migration in vitro in parallel with the downregulation of MMP expression. Only limited data are available for primary progressive multiple sclerosis (PPMS) which differs in demographic and immunological aspects as well as in MRI criteria from RRMS. In this study, 19 patients with laboratory-supported definite PPMS were treated with 8 x 10(6) IU IFN-beta1b (Betaferon(R)) subcutaneously every other day. Serum was collected before treatment and on months 1, 2, 3,6 and 9 during treatment. Levels of MMP-9 and of its natural inhibitor known as tissue-inhibitor of matrix-metalloproteinase-1 (TIMP-1) were quantified by ELISA. In addition MMP-2 serum levels were determined by zymography. 19 healthy volunteers served as controls. Before treatment serum levels of MMP-9 were elevated in patients with PPMS compared with controls, whereas there was no difference in TIMP-1 serum levels. During treatment with IFN-beta1b the concentration of MMP-9 in the serum of 18 out of 19 PPMS patients decreased, whereas serum levels of MMP-2 and TIMP-1 remained nearly unaffected. Our results demonstrate that the MMP-9 to TIMP-1 ratio in patients with PPMS is elevated in comparison with healthy controls. The suppression of MMP-9 by IFN-beta1b indicates that this drug is immunomodulatory active in PPMS patients. Further studies are necessary to test if IFN-beta exerts a beneficial effect in PPMS.