title: 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.
authors.affiliation: Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Dana
authors.initials: D
authors.lastname: Haves-Zburof
authors.forename: Tamar
authors.initials: T
authors.lastname: Paperna
authors.forename: Alumit
authors.initials: A
authors.lastname: Gour-Lavie
authors.forename: Ilana
authors.initials: I
authors.lastname: Mandel
authors.forename: Lea
authors.initials: L
authors.lastname: Glass-Marmor
authors.forename: Ariel
authors.initials: A
authors.lastname: Miller
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D055313:Cystatin B / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism*; D055316:Cystatin C / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology; D007962:Leukocytes / Q000166:cytology; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: D015415:Biomarkers; D055316:Cystatin C; D012333:RNA, Messenger; D016899:Interferon-beta; D055313:Cystatin B; D002403:Cathepsins; D002401:Cathepsin B; C028217:cathepsin S; D008775:Methylprednisolone