The selective proteasome inhibitors lactacystin and epoxomicin can be used to either up- or down-regulate antigen presentation at nontoxic doses.
The complete inhibition of proteasome activities interferes with the production of most MHC class I peptide ligands as well as with cellular proliferation and survival. In this study we have investigated how partial and selective inhibition of the chymotrypsin-like activity of the proteasome by the proteasome inhibitors lactacystin or epoxomicin would affect Ag presentation. At 0.5-1 microM lactacystin, the presentation of the lymphocytic choriomeningitis virus-derived epitopes NP118 and GP33 and the mouse CMV epitope pp89-168 were reduced and were further diminished in a dose-dependent manner with increasing concentrations. Presentation of the lymphocytic choriomeningitis virus-derived epitope GP276, in contrast, was markedly enhanced at low, but abrogated at higher, concentrations of either lactacystin or epoxomicin. The inhibitor-mediated effects were thus epitope specific and did not correlate with the degradation rates of the involved viral proteins. Although neither apoptosis induction nor interference with cellular proliferation was observed at 0.5-1 microM lactacystin in vivo, this concentration was sufficient to alter the fragmentation of polypeptides by the 20S proteasome in vitro. Our results indicate that partial and selective inhibition of proteasome activity in vivo is a valid approach to modulate Ag presentation, with potential applications for the treatment of autoimmune diseases and the prevention of transplant rejection.
Schwarz
K
K
Research Department, Cantonal Hospital St. Gall, St. Gallen, Switzerland.
de Giuli
R
R
Schmidtke
G
G
Kostka
S
S
van den Broek
M
M
Kim
K B
KB
Crews
C M
CM
Kraft
R
R
Groettrup
M
M
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects*; D000956:Antigens, Viral; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D006825:Hybridomas / Q000276:immunology / Q000378:metabolism; D006868:Hydrolysis / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects; D008217:Lymphocytic choriomeningitis virus / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism*; D009698:Nucleoproteins / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology / Q000633:toxicity; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014452:Ubiquitins / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology*; D014764:Viral Proteins
D000956:Antigens, Viral; D015853:Cysteine Proteinase Inhibitors; D006023:Glycoproteins; D009097:Multienzyme Complexes; D009698:Nucleoproteins; D009842:Oligopeptides; D010446:Peptide Fragments; D014452:Ubiquitins; D014764:Viral Proteins; C094244:glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus; C094246:nucleoprotein peptide 118-126, lymphocytic choriomeningitis virus; C067713:lactacystin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine; C078846:epoxomicin