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.
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.
Zhang
T
T
Department of Parasitology and Immunology, University of Tokushima, Tokushima, Japan.
Maekawa
Y
Y
Yasutomo
K
K
Ishikawa
H
H
Fawzy Nashed
B
B
Dainichi
T
T
Hisaeda
H
H
Sakai
T
T
Kasai
M
M
Mizuochi
T
T
Asao
T
T
Katunuma
N
N
Himeno
K
K
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D017951:Antigen Presentation / Q000276:immunology* / Q000502:physiology; D000938:Antigen-Presenting Cells / Q000276:immunology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology / Q000378:metabolism*; D000953:Antigens, Protozoan / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D002455:Cell Division / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism; D004151:Dipeptides / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism*; D018320:Leishmania major; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy / Q000276:immunology*; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D010436:Pepstatins / Q000494:pharmacology / Q000627:therapeutic use; D018417:Th1 Cells / Q000187:drug effects; D018418:Th2 Cells / Q000187:drug effects
D000944:Antigens, Differentiation, B-Lymphocyte; D000953:Antigens, Protozoan; C400541:CA 074 methyl ester; D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D004151:Dipeptides; D000949:Histocompatibility Antigens Class II; D010436:Pepstatins; C045084:invariant chain; C014195:Streptomyces pepsin inhibitor; D002401:Cathepsin B; D016282:Aspartic Acid Endopeptidases; C031375:pepstatin