2002/03/01 by Thomas M. Zollner, Maurizio Podda, Christine Pien +3 · 1 citation
Immunology and Microbiology · Biochemistry, Genetics and Molecular Biology · #Immunodeficiency and Autoimmune Disorders #Ubiquitin and proteasome pathways #NF-κB Signaling Pathways
paper · doi:10.1172/jci12736
openalex publication_date 2002/03/01 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
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.