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: Dana Haves-Zburof, Tamar Paperna, Alumit Gour-Lavie, Ilana Mandel, Lea Glass-Marmor, Ariel Miller
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 15 Issue 11 Pg. 2421-9 (Nov 2011) ISSN: 1582-4934 [Electronic] England
• PMID: 21143385 (Publication Type: Journal Article)
• Copyright: © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Chemical References

• Biomarkers
• Cystatin C
• RNA, Messenger
• Interferon-beta
• Cystatin B
• Cathepsins
• Cathepsin B
• cathepsin S
• Methylprednisolone

Topics

• Adolescent
• Adult
• Biomarkers
• Cathepsin B (antagonists & inhibitors, biosynthesis, metabolism)
• Cathepsins (antagonists & inhibitors, biosynthesis, metabolism)
• Cystatin B (biosynthesis, blood, metabolism)
• Cystatin C (biosynthesis, blood, metabolism)
• Disease Progression
• Female
• Humans
• Interferon-beta (pharmacology)
• Leukocytes (cytology)
• Male
• Methylprednisolone (pharmacology)
• Middle Aged
• Multiple Sclerosis (drug therapy, metabolism, pathology)
• RNA, Messenger (biosynthesis)