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.