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

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.

• Authors: Thomas M Zollner, Maurizio Podda, Christine Pien, Peter J Elliott, Roland Kaufmann, Wolf-Henning Boehncke
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 109 Issue 5 Pg. 671-9 (Mar 2002) ISSN: 0021-9738 [Print] United States
• PMID: 11877475 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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