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Scientific article
English

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

Published inThe Journal of clinical investigation, vol. 109, no. 5, p. 671-679
Publication date2002
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-kappa B for maximal trans-activation. PS-519 is a potent and selective proteasome inhibitor based upon the naturally occurring compound lactacystin, which inhibits NF-kappa B activation by blocking the degradation of its inhibitory protein I kappa B. 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.

Keywords
  • Acetylcysteine/*analogs & derivatives/pharmacology
  • Animals
  • Antigens, CD/metabolism
  • Antigens, Differentiation, T-Lymphocyte/metabolism
  • *Bacterial Toxins
  • Cysteine Endopeptidases
  • Cysteine Proteinase Inhibitors/pharmacology
  • DNA/drug effects/metabolism
  • Disease Models, Animal
  • Enterotoxins/immunology
  • HLA-DR Antigens/metabolism
  • Humans
  • Lectins, C-Type
  • Lymphocyte Activation/drug effects
  • Mice
  • Mice, SCID
  • Multienzyme Complexes/*antagonists & inhibitors
  • NF-kappa B/metabolism
  • Proteasome Endopeptidase Complex
  • Psoriasis/drug therapy/enzymology/*immunology/pathology
  • Receptors, Interleukin-2/metabolism
  • Skin Transplantation/immunology
  • Superantigens/*metabolism
  • T-Lymphocytes/drug effects/*immunology
  • Transplantation, Heterologous
Affiliation Not a UNIGE publication
Citation (ISO format)
ZOLLNER, Thomas Matthias et al. Proteasome inhibition reduces superantigen-mediated T cell activation and the severity of psoriasis in a SCID-hu model. In: The Journal of clinical investigation, 2002, vol. 109, n° 5, p. 671–679. doi: 10.1172/JCI12736
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Identifiers
ISSN of the journal0021-9738
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