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Proteasome inhibition reduces superantigen-mediated T cell activation and the severity of psoriasis in a SCID-hu model
Thomas M. Zollner, … , Roland Kaufmann, Wolf-Henning Boehncke
Thomas M. Zollner, … , Roland Kaufmann, Wolf-Henning Boehncke
Published March 1, 2002
Citation Information: J Clin Invest. 2002;109(5):671-679. https://doi.org/10.1172/JCI12736.
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Article Genetics Article has an altmetric score of 9

Proteasome inhibition reduces superantigen-mediated T cell activation and the severity of psoriasis in a SCID-hu model

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Abstract

There is increasing evidence that bacterial superantigens contribute to inflammation and T cell responses in psoriasis. Psoriatic inflammation entails a complex series of inductive and effector processes that require the regulated expression of various proinflammatory genes, many of which require NF-κB for maximal trans-activation. PS-519 is a potent and selective proteasome inhibitor based upon the naturally occurring compound lactacystin, which inhibits NF-κB activation by blocking the degradation of its inhibitory protein IκB. We report that proteasome inhibition by PS-519 reduces superantigen-mediated T cell–activation in vitro and in vivo. Proliferation was inhibited along with the expression of very early (CD69), early (CD25), and late T cell (HLA-DR) activation molecules. Moreover, expression of E-selectin ligands relevant to dermal T cell homing was reduced, as was E-selectin binding in vitro. Finally, PS-519 proved to be therapeutically effective in a SCID-hu xenogeneic psoriasis transplantation model. We conclude that inhibition of the proteasome, e.g., by PS-519, is a promising means to treat T cell–mediated disorders such as psoriasis.

Authors

Thomas M. Zollner, Maurizio Podda, Christine Pien, Peter J. Elliott, Roland Kaufmann, Wolf-Henning Boehncke

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Figure 3

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PS-519 inhibits TSST-1–induced expression of T cell activation molecules...
PS-519 inhibits TSST-1–induced expression of T cell activation molecules. PBMCs were stimulated with TSST-1 (100 ng/ml) in the presence or absence of PS-519 (0.25–2.5 μg/ml). CD69+ CD3+ (a), CD25+ CD3+ (b), and HLA-DR+ CD3+ (c) surface expression was measured at days 1, 3, 5, 7, and 9 (days 7 and 9 not shown) by flow cytometry. Appropriate isotype Ig’s served as controls to set gates for positive and negative staining. For CD69 expression, significant reduction was observed on day 1 starting at 1.0 μg/ml (P < 0.05), and on days 3 and 5 starting at 0.5 μg/ml PS-519 (P < 0.001 and P < 0.05, respectively). For CD25 expression, significant reduction was observed on day 3 starting at 1.0 μg/ml (P < 0.001), and on day 5 starting at 0.25 μg/ml PS-519 (P < 0.001). For HLA-DR expression, significant reduction was observed on day 1 at 2.5 μg/ml (P < 0.05), on day 3 starting at 1.0 μg/ml (P < 0.05), and on day 5 starting at 0.25 μg/ml PS-519 (P < 0.001). Data represent means of five experiments ± SD.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 42 patents
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