The selective proteasome inhibitors lactacystin and epoxomicin can be used to either up- or down-regulate antigen presentation at nontoxic doses

Item Type:	Article
Title:	The selective proteasome inhibitors lactacystin and epoxomicin can be used to either up- or down-regulate antigen presentation at nontoxic doses
Creators Name:	Schwarz, K. and de Giuli, R. and Schmidtke, G. and Kostka, S. and van den Broek, M. and Kim, K.B. and Crews, C.M. and Kraft, R. and Groettrup, M.
Abstract:	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 μM 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 μM 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.
Keywords:	Acetylcysteine, Amino Acid Sequence, Antigen Presentation, Apoptosis, Cell Division, Cell Line, Cultured Tumor Cells, Cysteine Endopeptidases, Cysteine Proteinase Inhibitors, Cytotoxic T-Lymphocytes, Down-Regulation, Glycoproteins, Hybridomas, Hydrolysis, Immunologic Dose-Response Relationship, Inbred BALB C Mice, Inbred C57BL Mice, Lymphocyte Activation, Lymphocytic choriomeningitis virus, Molecular Sequence Data, Multienzyme Complexes, Nucleoproteins, Oligopeptides, Peptide Fragments, Proteasome Endopeptidase Complex, Ubiquitins, Up-Regulation, Viral Antigens, Viral Proteins, Animals, Mice
Source:	Journal of Immunology
ISSN:	0022-1767
Publisher:	American Association of Immunologists
Volume:	164
Number:	12
Page Range:	6147-6157
Date:	15 June 2000
Official Publication:	http://www.jimmunol.org/cgi/content/abstract/164/12/6147
PubMed:	View item in PubMed

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