[Proposed mechanism of action of metalloendopeptidase-F in the treatment of patients with chronic hepatitis B or C infection].
Chronic hepatitis B and C virus infections have been characterized by the pathophysiological features with a high incidence of progression to cirrhosis and development of hepatocellular carcinoma. The viral persistence produced by escape mutations from virus-specific cytotoxic T lymphocytes (CTL) response may lead to upregulation of delayed-type hypersensitivity immune response, which causes hepatic tissue damage through non specific macrophage activation and CTL response and promotes pathogenesis of hepatic fibrosis. In a preliminary clinical study, a novel metalloendopeptidase-F (MEP-F) has been shown to be effective in the treatment of patients with either chronic hepatitis B or C infection. Oral administration of MEP-F resulted in a significant reduction of the serum levels of HBs antigen and HCV RNA and improvement in the liver function abnormalities. However, the mechanism of action of MEP-F is not yet well understood. There are accumulating evidences showing an important role of alpha 2-macroglobulin-proteinase complexes in regulatory mechanisms of immune response and repairing within impaired and inflammatory tissues. In this article, reviewing the pharmacological and biological properties of alpha 2-macroglobulin-proteinase complexes, the mechanism of anti-viral effect of MEP-F is examined based on the clinical findings. It is indicated that alpha 2-macroglobulin-MEP-F complexes may induce macrophage/Kuppfer cell activation and proliferation through binding their receptors on the cells and activating signaling cascades, which enhance both anti-viral specific and nonspecific immune responses. alpha 2-Macroglobulin-MEP-F complexes may also augment cellular immunity and hepatic regeneration by neutralizing the immunosuppressive and fibrogenic activities of transforming growth factor-beta.
Fujisaki
S
S
Institute of Enzyme Research, Osaka, Japan.
Fujisaki
T
T
Yoshida
J
J
Fujisaki
Y
Y
Mitani
M
M
Nakamura
M
M
Otake
N
N
D000818:Animals; D016207:Cytokines / Q000378:metabolism / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000276:immunology / Q000628:therapy*; D019698:Hepatitis C, Chronic / Q000276:immunology / Q000628:therapy*; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000502:physiology; D008115:Liver Regeneration; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008264:Macrophages / Q000276:immunology; D008666:Metalloendopeptidases / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D011971:Receptors, Immunologic / Q000378:metabolism / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D000511:alpha-Macroglobulins / Q000378:metabolism / Q000502:physiology
D016207:Cytokines; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011971:Receptors, Immunologic; D016212:Transforming Growth Factor beta; D000511:alpha-Macroglobulins; D008666:Metalloendopeptidases; C412013:metalloendopeptidase F