Novel physiological functions of cathepsins B and L on antigen processing and osteoclastic bone resorption.
Lysosomal cathepsin B plays an essential role in the processing of ovalbumin as an exogenous antigen to produce the complex between antigenic-peptide and major histocompatibility-complex class II. Administration of cathepsin B inhibitors, E-64, CA-074 and vitamin B6, caused the strong suppression of the Th-2 type immune responses. We found that pyridoxal phosphate (PAP), a coenzyme form of vitamin B6, inhibits the activities of cathepsin B and L in vitro and vitamin B6 administration induces the inhibition of the lysosomal cathepsin activities in vivo. The production of an antigenic epitope (I323-R339) of ovalbumin by antigen presenting cells was suppressed by cathepsin B specific inhibitors. The ovalbumin dependent production of immunoglobulins (IgE and IgG1) and of the corresponding interleukin (IL-4) was suppressed by cathepsin B inhibitors, while the production of IgG2a and interferon (INF-gamma) was increased. The switch of helper T lymphocyte functions from the type-2 to the type-1 may be induced by the cathepsin B inhibition. The experimental bone pit formation, i.e., osteoclastic bone collagen degradation test, induced by parathyroid hormone was markedly suppressed by the administration of pyridoxal, because of the inhibition of cathepsin L type cysteine proteases in bone.
Tokushima Bunri University, Institute for Health Sciences, Japan.
N
N
Katunuma
Y
Y
Matsunaga
A
A
Matsui
H
H
Kakegawa
K
K
Endo
T
T
Inubushi
T
T
Saibara
Y
Y
Ohba
T
T
Kakiuchi
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D001402:B-Lymphocytes / Q000201:enzymology; D001862:Bone Resorption / Q000201:enzymology*; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology; D010450:Endopeptidases; D000939:Epitopes / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007700:Kinetics; D008247:Lysosomes / Q000201:enzymology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D010047:Ovalbumin / Q000276:immunology; D011736:Pyridoxine / Q000031:analogs & derivatives / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014170:Transformation, Genetic / Q000235:genetics
D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D000939:Epitopes; D007166:Immunosuppressive Agents; D010047:Ovalbumin; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse; D011736:Pyridoxine