Cysteine cathepsin S as an immunomodulatory target: present and future trends

Objective: Antigen presentation is the key to immune response. Cathepsin S plays a major role in the degradation of the invariant peptide chain associated with the major histocompatibility complex and thus affects antigen presentation. This review will focus on the recent developments made in field of cysteine cathepsins especially cathepsin S and their future prospects as a therapeutic target. Methods: Selective cathepsin inhibitors for targeting autoimmune disorders, atherosclerosis, osteoporosis, osteoarthritis and cancer are being pursued by many pharmaceutical companies. Recent publications in this field have been used as references to evaluate the current and future trends in cathepsin S inhibitors as an immunomodulatory target. Conclusions: The temporal and spatial position occupied by cathepsin S in immune presentation, gives rise to the hope that an inhibitor would impart selectivity with a lesser propensity for side effects than other immunosuppressive agents.

[1]  C. Pham,et al.  Dipeptidyl peptidase I activates neutrophil-derived serine proteases and regulates the development of acute experimental arthritis. , 2002, The Journal of clinical investigation.

[2]  S. Stevanović,et al.  Cathepsin V is involved in the degradation of invariant chain in human thymus and is overexpressed in myasthenia gravis. , 2003, The Journal of clinical investigation.

[3]  T. Chambers,et al.  Recent developments in cathepsin K inhibitor design. , 2005, Current opinion in drug discovery & development.

[4]  C. Peters,et al.  The lysosomal cysteine protease cathepsin L regulates keratinocyte proliferation by control of growth factor recycling , 2005, Journal of Cell Science.

[5]  Robert W. Thompson,et al.  Critical role of dipeptidyl peptidase I in neutrophil recruitment during the development of experimental abdominal aortic aneurysms , 2007, Proceedings of the National Academy of Sciences.

[6]  B. Turk,et al.  Cysteine cathepsins in the immune response. , 2006, Tissue antigens.

[7]  T. Ley,et al.  Dipeptidyl peptidase I is required for the processing and activation of granzymes A and B in vivo. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[8]  H. Chapman,et al.  Emerging roles for cysteine proteases in human biology. , 1997, Annual review of physiology.

[9]  H. Kirschke,et al.  Secretion of a latent, acid activatable cathepsin L precursor by human non-small cell lung cancer cell lines. , 1993, Oncology research.

[10]  Martin Deeg,et al.  Cathepsin S and an asparagine‐specific endoprotease dominate the proteolytic processing of human myelin basic protein in vitro , 2001, European journal of immunology.

[11]  H. Chapman,et al.  Endosomal proteases in antigen presentation. , 2006, Current opinion in immunology.

[12]  K. Clément,et al.  Emerging role of cathepsin S in obesity and its associated diseases , 2007, Clinical chemistry and laboratory medicine.

[13]  H. Kirschke,et al.  [34] Cathepsin S and related lysosomal endopeptidases , 1994 .

[14]  Christoph Peters,et al.  Cathepsin L Deficiency Reduces Diet-Induced Atherosclerosis in Low-Density Lipoprotein Receptor-Knockout Mice , 2007, Circulation.

[15]  D. White,et al.  An orally active reversible inhibitor of cathepsin S inhibits human trans vivo delayed-type hypersensitivity. , 2006, European journal of pharmacology.

[16]  H. Ploegh,et al.  Role for Cathepsin F in Invariant Chain Processing and Major Histocompatibility Complex Class II Peptide Loading by Macrophages , 2000, The Journal of experimental medicine.

[17]  J. Deussing,et al.  Cathepsins B and D are dispensable for major histocompatibility complex class II-mediated antigen presentation. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[18]  J. Koo,et al.  Update on the mechanisms and efficacy of biological therapies for psoriasis. , 2005, Journal of dermatological science.

[19]  H. Kirschke,et al.  Cathepsin S and related lysosomal endopeptidases. , 1994, Methods in enzymology.

[20]  P. Libby,et al.  Deficiency of the Cysteine Protease Cathepsin S Impairs Microvessel Growth , 2003, Circulation research.

[21]  Ranjeny Thomas,et al.  Dendritic cells: The driving force behind autoimmunity in rheumatoid arthritis? , 1999, Immunology and cell biology.

[22]  W. L. Benedict,et al.  Multiple Sclerosis , 2007, Journal - Michigan State Medical Society.

[23]  D. Brömme,et al.  Collagenolytic activity of cathepsin K is specifically modulated by cartilage-resident chondroitin sulfates. , 2000, Biochemistry.

[24]  J. Palmer,et al.  The effects of fluoromethyl ketone inhibitors of cathepsin B on adjuvant induced arthritis. , 1993, The Journal of rheumatology.

[25]  J. Link,et al.  Advances in cathepsin S inhibitor design. , 2006, Current opinion in drug discovery & development.

[26]  D. Brömme,et al.  The role of cathepsins in osteoporosis and arthritis: rationale for the design of new therapeutics. , 2005, Advanced drug delivery reviews.

[27]  R. Lucius,et al.  Cystatins Up-regulate Nitric Oxide Release from Interferon-γ- activated Mouse Peritoneal Macrophages* , 1996, The Journal of Biological Chemistry.

[28]  T. Welte,et al.  Lysosomal cysteine proteases in the lung: role in protein processing and immunoregulation , 2004, European Respiratory Journal.

[29]  P. Libby,et al.  Cystatin C deficiency in human atherosclerosis and aortic aneurysms. , 1999, The Journal of clinical investigation.

[30]  P. Henkart,et al.  Surface Cathepsin B Protects Cytotoxic Lymphocytes from Self-destruction after Degranulation , 2002, The Journal of experimental medicine.

[31]  Georg Schett,et al.  Cytokines in the pathogenesis of rheumatoid arthritis , 2007, Nature Reviews Immunology.

[32]  I. Kola,et al.  Cathepsin K Knockout Mice Develop Osteopetrosis Due to a Deficit in Matrix Degradation but Not Demineralization , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[33]  G. Dranoff,et al.  Cathepsin S required for normal MHC class II peptide loading and germinal center development. , 1999, Immunity.

[34]  Christoph Peters,et al.  Dilated cardiomyopathy in mice deficient for the lysosomal cysteine peptidase cathepsin L , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[35]  D. Turk,et al.  Structural and functional aspects of papain-like cysteine proteinases and their protein inhibitors. , 1997, Biological chemistry.

[36]  Christoph Peters,et al.  Cathepsin L Regulates CD4+ T Cell Selection Independently of Its Effect on Invariant Chain , 2002, The Journal of experimental medicine.

[37]  A. Melms,et al.  Thymus and myasthenia gravis: antigen processing in the human thymus and the consequences for the generation of autoreactive T cells , 2006, Acta neurologica Scandinavica. Supplementum.

[38]  J. Glickman,et al.  Mannose 6-phosphate-independent targeting of lysosomal enzymes in I- cell disease B lymphoblasts , 1993, The Journal of cell biology.

[39]  S. Bevan,et al.  Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain , 2007, Proceedings of the National Academy of Sciences.

[40]  I. van der Made,et al.  Disruption of the Cathepsin K Gene Reduces Atherosclerosis Progression and Induces Plaque Fibrosis but Accelerates Macrophage Foam Cell Formation , 2005, Circulation.

[41]  K. Clément,et al.  Cathepsin L activity controls adipogenesis and glucose tolerance , 2007, Nature Cell Biology.

[42]  P. Wolters,et al.  Regulated Expression, Processing, and Secretion of Dog Mast Cell Dipeptidyl Peptidase I* , 1998, The Journal of Biological Chemistry.

[43]  H. Chapman,et al.  Murine Cathepsin F Deficiency Causes Neuronal Lipofuscinosis and Late-Onset Neurological Disease , 2006, Molecular and Cellular Biology.

[44]  O. Vasiljeva,et al.  Recombinant human procathepsin S is capable of autocatalytic processing at neutral pH in the presence of glycosaminoglycans , 2005, FEBS letters.

[45]  J. Deussing,et al.  Thyroid functions of mouse cathepsins B, K, and L. , 2003, The Journal of clinical investigation.

[46]  W. Parks Who are the proteolytic culprits in vascular disease? , 1999, The Journal of clinical investigation.

[47]  J. Kos,et al.  Cysteine cathepsins: regulators of antitumour immune response , 2006, Expert opinion on biological therapy.

[48]  M. Melli,et al.  New insights into the molecular basis of progressive myoclonus epilepsy: a multiprotein complex with cystatin B. , 2002, Human molecular genetics.

[49]  E. Keystone Abandoned therapies and unpublished trials in rheumatoid arthritis , 2003, Current opinion in rheumatology.

[50]  J. Palmer,et al.  Cysteine proteinase inhibitors decrease articular cartilage and bone destruction in chronic inflammatory arthritis. , 1994, Arthritis and rheumatism.

[51]  A. Rudensky,et al.  Impaired invariant chain degradation and antigen presentation and diminished collagen-induced arthritis in cathepsin S null mice. , 1999, Immunity.

[52]  Lars Karlsson,et al.  Identification of a Potent and Selective Noncovalent Cathepsin S Inhibitor , 2004, Journal of Pharmacology and Experimental Therapeutics.

[53]  J. Kos,et al.  Nanoscale polymer carriers to deliver chemotherapeutic agents to tumours , 2005, Expert opinion on biological therapy.

[54]  Makoto Naito,et al.  Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice. , 2003, The Journal of clinical investigation.

[55]  Richard,et al.  Role of cathepsin S-dependent epithelial cell apoptosis in IFN-γ-induced alveolar remodeling and pulmonary emphysema , 2005, The Journal of Immunology.

[56]  A. Bucht,et al.  Increased levels of hypoxia-sensitive proteins in allergic airway inflammation. , 2004, American journal of respiratory and critical care medicine.

[57]  M. James,et al.  Effects of disease-modifying anti-rheumatic drugs (DMARDs) on the activities of rheumatoid arthritis-associated cathepsins K and S , 2007, Biological chemistry.

[58]  S. Weiss,et al.  Regulation of Elastinolytic Cysteine Proteinase Activity in Normal and Cathepsin K–Deficient Human Macrophages , 2000, The Journal of experimental medicine.

[59]  C. Pham,et al.  Characterization of Murine Cathepsin W and Its Role in Cell-mediated Cytotoxicity* , 2004, Journal of Biological Chemistry.

[60]  A. Pinchera,et al.  Cathepsin K Null Mice Show Reduced Adiposity during the Rapid Accumulation of Fat Stores , 2007, PloS one.

[61]  R. Thurmond,et al.  Cathepsin S inhibitors as novel immunomodulators. , 2005, Current opinion in investigational drugs.

[62]  P. Wolters,et al.  Importance of lysosomal cysteine proteases in lung disease , 2000, Respiratory research.

[63]  H. Galadari,et al.  Psoriasis: a fresh look. , 2005, Clinics in dermatology.

[64]  A. Rudensky,et al.  Cathepsin L: critical role in Ii degradation and CD4 T cell selection in the thymus. , 1998, Science.

[65]  J. Deussing,et al.  Cathepsin L deficiency as molecular defect of furless: hyperproliferation of keratinocytes and pertubation of hair follicle cycling , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[66]  R. Mitchell,et al.  Cathepsin S activity regulates antigen presentation and immunity. , 1998, The Journal of clinical investigation.

[67]  S. Stevanović,et al.  Specificity of human cathepsin S determined by processing of peptide substrates and MHC class II-associated invariant chain , 2006, Biological chemistry.