Cathepsins and their endogenous inhibitors cystatins: expression and modulation in multiple sclerosis.
Bottom Line: Cathepsins are involved in a variety of physiological processes including antigen processing and presentation and extracellular matrix degradation.In the present study, we evaluated whether expression levels of cathepsins S and B and their inhibitors cystatins B and C are affected by multiple sclerosis (MS) disease state (relapse and remission) and therapies (interferon-β [IFN-β] and the glucocorticoid [GC] methylprednisolone), and whether they are associated with the IFN-β response phenotype.Interestingly, pre-treatment serum cathepsin S/cystatin C ratio was higher in 'good responders' to IFN-β therapy compared to patients without a good response (by 94%, P = 0.003).
Affiliation: Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.Show MeSH
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Mentions: Following the pharmacogenetics study which reported association of the CTSS gene with IFN-β response in MS , and our observation that IFN-β seems to reduce cathepsin S serum protein levels (above), we assessed cathepsin S and its inhibitors’ expression with respect to the IFN-β treatment response phenotype in the patient cohort. Pre-treatment levels of cathepsin S were higher in RNA from PBLs of patients classified as ‘good responders’ (n= 12) compared to the ‘others’ group (n= 11), shown in Figure 4A; however, this trend did not reach statistical significance. Differences for CTSB, CSTB (not shown) and CSTC (Fig. 4A), or any of the ratios of the proteases to their inhibitors, were not significant. Interestingly, the pre-treatment serum protein levels of the inhibitor cystatin C were correlated with response status, and were significantly lower in the ‘good responders’ group (64% higher levels in the ‘others group versus the ‘good responder’ group, n= 10 and n= 14, respectively, P= 0.004, Fig. 4B). The sensitivity and specificity for detecting a good responder was 71% and 90%, respectively, using 809 ng/ml as a cut-off value [Area under curve (AUC) = 0.850 ± 0.079, P= 0.004]. The protein ratio cathepsin S/cystatin C in the serum, reflecting the balance of the proteolytic activity for cathepsin S, was significantly higher in ‘good responders’ prior to treatment initiation (by 94%, P= 0.003) (Fig. 4C).
Affiliation: Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.