Cathepsins and their endogenous inhibitors cystatins: expression and modulation in multiple sclerosis

Abstract

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. Real-time PCR was employed to compare RNA expression levels in peripheral blood leucocytes (PBLs) and ELISA to determine serum protein levels of MS patients and matched healthy individuals. Cathepsin S RNA was higher in MS patients in the relapse state compared to controls (by 74%, P= 3 × 10−5, n= 30 versus n= 18) with a similar increase observed in serum (66%, P= 0.002, n= 18 versus n= 20). GC treatment reduced cathepsin S levels in PBL RNA (by 44%, P= 6 × 10−6, n= 27) and serum proteins (by 27%, P= 1 × 10−5, n= 26), reduced the serum protein levels of pro-cathepsin B (by 8%, P= 0.0007, n= 23), and in parallel increased the serum levels of their inhibitor cystatin C (by 82%, P= 8 × 10−6, n= 26). IFN-β therapy significantly elevated the RNA levels (n= 16) of cathepsin B (by 16%, P= 0.03), cystatin B (44%, P= 0.004) and cystatin C (48%, P= 0.011). In the serum, only cathepsin S levels were reduced by IFN-β (16%, P= 0.006, n= 25). 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). These results suggest that cathepsin S and cystatin C may contribute to disease activity in MS, specifically in a subgroup of patients that are responsive to IFN-β therapy, and that these proteins should be further evaluated as biomarkers in MS.

Cathepsin S: therapeutic, diagnostic, and prognostic potential

“…More recently, this initial mechanistic work has been complemented by clinical studies, where an increase in cathepsin S expression at both transcriptional and translational levels was revealed in MS patients. Relapsing-remitting MS (RR-MS) patients showed a 74% and 66% increase in cathepsin S expression vs. normal controls with regards to RNA expression and serum protein levels respectively ( Haves-Zburof et al, 2011).…”

The Emerging Relevance of the Cysteine Protease Cathepsin S in Disease

“…Clinically, CatS has been shown to be significantly up-regulated in circulating leucocytes isolated from MS patients [63]. Genetic analysis of interferon-inducible genes highlighted a single-nucleotide polymorphism (SNP) within the promoter for the catS gene and interferon-b treatment responsiveness in MS patients [64].…”

Brain inflammation is accompanied by peripheral inflammation in Cstb −/− mice, a model for progressive myoclonus epilepsy

“…EPM1 is caused by loss-of-function mutations in the cystatin B ( CSTB ) gene [2, 3], which encodes an inhibitor of lysosomal cysteine cathepsins [4]. CSTB is highly expressed in immune cells, e.g., in blood leukocytes, hepatic lymphocytes, placental macrophages, and microglia [5–9], and it is upregulated in vitro by pro-inflammatory stimulation [8, 10, 11]. In immune cells, the function of CSTB has been linked to chemotaxis [8], expression and secretion of cytokines, and release of nitric oxide [10, 12, 13], implying a role in the immune response.…”