Pepstatin A-sensitive aspartic proteases in lysosome are involved in degradation of the invariant chain and antigen-processing in antigen presenting cells of mice infected with Leishmania major

Biochem Biophys Res Commun. 2000 Sep 24;276(2):693-701. doi: 10.1006/bbrc.2000.3538.

Abstract

We previously reported that CA074, a specific inhibitor of cathepsin B, significantly deviated immune responses from the disease-promoting Th2 type to the protective Th1 type in BALB/c mice infected with Leishmania major. Herein, we found that pepstatin A-sensitive aspartic proteases (PSAP) in lysosomes seem to play a different role from that of cathepsin B in antigen-processing and Ii-degradation. That is, cathepsin B appears to digest 16-, 28-, and 31-kDa peptides of soluble leishmania antigen (SLA), whereas PSAP seems to process mainly 28-kDa peptides. Furthermore, the latter protease contributed to the degradation of Ii but cathepsin B did not. Following treatment with pepstatin A, both Th1 and Th2 responses were profoundly suppressed in resistant DBA/2 mice (H-2(d)) and in susceptible BALB/c mice (H-2(d)), and both strains of mice became markedly susceptible compared with the untreated groups, probably owing to failure in degradation of Ii and partly to failure in digestion of 28-kDa peptide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibody Formation / drug effects
  • Antigen Presentation / immunology*
  • Antigen Presentation / physiology
  • Antigen-Presenting Cells / immunology*
  • Antigens, Differentiation, B-Lymphocyte / immunology
  • Antigens, Differentiation, B-Lymphocyte / metabolism*
  • Antigens, Protozoan / metabolism
  • Aspartic Acid Endopeptidases / antagonists & inhibitors
  • Aspartic Acid Endopeptidases / metabolism*
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / metabolism
  • Cathepsin B / antagonists & inhibitors
  • Cell Division / drug effects
  • Cysteine Proteinase Inhibitors / therapeutic use
  • Cytokines / metabolism
  • Dipeptides / therapeutic use
  • Disease Models, Animal
  • Female
  • Histocompatibility Antigens Class II / immunology
  • Histocompatibility Antigens Class II / metabolism*
  • Leishmania major*
  • Leishmaniasis, Cutaneous / drug therapy
  • Leishmaniasis, Cutaneous / immunology*
  • Lymphocytes / drug effects
  • Lymphocytes / pathology
  • Lysosomes / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred DBA
  • Pepstatins / pharmacology
  • Pepstatins / therapeutic use
  • Th1 Cells / drug effects
  • Th2 Cells / drug effects

Substances

  • Antigens, Differentiation, B-Lymphocyte
  • Antigens, Protozoan
  • CA 074 methyl ester
  • Cysteine Proteinase Inhibitors
  • Cytokines
  • Dipeptides
  • Histocompatibility Antigens Class II
  • Pepstatins
  • invariant chain
  • Streptomyces pepsin inhibitor
  • Cathepsin B
  • Aspartic Acid Endopeptidases
  • pepstatin