Journal Article

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

Haves‐Zburof, Dana, Glass‐Marmor, Lea, Miller, Ariel, Mandel, Ilana, Paperna, Tamar, Gour‐Lavie, Alumit

2011

Overview

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.

• Publisher: Blackwell Publishing Ltd,John Wiley & Sons, Inc
• Subject: Adolescent / Adult / Antigen presentation / Antigen processing / biomarker / Biomarkers / Blood levels / Cathepsin B / Cathepsin B - antagonists & inhibitors / Cathepsin B - biosynthesis / Cathepsin B - metabolism / Cathepsin S / Cathepsins / Cathepsins - antagonists & inhibitors / Cathepsins - biosynthesis / Cathepsins - metabolism / Cystatin B - biosynthesis / Cystatin B - blood / Cystatin B - metabolism / Cystatin C / Cystatin C - biosynthesis / Cystatin C - blood / Cystatin C - metabolism / cystein protease / Disease Progression / Extracellular matrix / Female / glucocorticoids / Humans / Interferon-beta - pharmacology / interferon‐β / Leukocytes / Leukocytes - cytology / Male / Methylprednisolone / Methylprednisolone - pharmacology / Middle Aged / Multiple sclerosis / Multiple Sclerosis - drug therapy / Multiple Sclerosis - metabolism / Multiple Sclerosis - pathology / Original / Patients / Peptides / Peripheral blood / Phenotypes / Proteins / Remission / Remission (Medicine) / Ribonucleic acid / RNA / RNA, Messenger - biosynthesis / Serum levels / Serum proteins / β-Interferon