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

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2000
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Schwarz, Katrin
Giuli, Rita de
Kostka, Susanne
Broek, Maries van den
Kim, Kyung Bo
Crews, Craig M.
Kraft, Regine
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The Journal of Immunology. 2000, 164(12), pp. 6147-6157. ISSN 0022-1767. eISSN 1550-6606. Available under: doi: 10.4049/​jimmunol.164.12.6147
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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.

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ISO 690SCHWARZ, Katrin, Rita de GIULI, Gunter SCHMIDTKE, Susanne KOSTKA, Maries van den BROEK, Kyung Bo KIM, Craig M. CREWS, Regine KRAFT, Marcus GRÖTTRUP, 2000. The selective proteasome inhibitors lactacystin and epoxomicin can be used to either up- or down-regulate antigen presentation at nontoxic doses. In: The Journal of Immunology. 2000, 164(12), pp. 6147-6157. ISSN 0022-1767. eISSN 1550-6606. Available under: doi: 10.4049/​jimmunol.164.12.6147
BibTex
@article{Schwarz2000selec-22166,
  year={2000},
  doi={10.4049/​jimmunol.164.12.6147},
  title={The selective proteasome inhibitors lactacystin and epoxomicin can be used to either up- or down-regulate antigen presentation at nontoxic doses},
  number={12},
  volume={164},
  issn={0022-1767},
  journal={The Journal of Immunology},
  pages={6147--6157},
  author={Schwarz, Katrin and Giuli, Rita de and Schmidtke, Gunter and Kostka, Susanne and Broek, Maries van den and Kim, Kyung Bo and Crews, Craig M. and Kraft, Regine and Gröttrup, Marcus}
}
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