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

J Clin Invest. 2002 Mar;109(5):671-9. doi: 10.1172/JCI12736.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / analogs & derivatives*
  • Acetylcysteine / pharmacology
  • Animals
  • Antigens, CD / metabolism
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • Bacterial Toxins*
  • Cysteine Endopeptidases
  • Cysteine Proteinase Inhibitors / pharmacology
  • DNA / drug effects
  • DNA / 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
  • Psoriasis / enzymology
  • Psoriasis / immunology*
  • Psoriasis / pathology
  • Receptors, Interleukin-2 / metabolism
  • Skin Transplantation / immunology
  • Superantigens / metabolism*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • Transplantation, Heterologous

Substances

  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • Bacterial Toxins
  • CD69 antigen
  • Cysteine Proteinase Inhibitors
  • Enterotoxins
  • HLA-DR Antigens
  • Lectins, C-Type
  • Multienzyme Complexes
  • NF-kappa B
  • PS519
  • Receptors, Interleukin-2
  • Superantigens
  • enterotoxin F, Staphylococcal
  • DNA
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • Acetylcysteine