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

Zollner, Thomas Matthias
Podda, Maurizio
Pien, Christine
Elliott, Peter J.
Kaufmann, Roland
Published in Journal of Clinical Investigation. 2002, vol. 109, no. 5, p. 671-679
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/pharmacologyAnimalsAntigens, CD/metabolismAntigens, Differentiation, T-Lymphocyte/metabolism*Bacterial ToxinsCysteine EndopeptidasesCysteine Proteinase Inhibitors/pharmacologyDNA/drug effects/metabolismDisease Models, AnimalEnterotoxins/immunologyHLA-DR Antigens/metabolismHumansLectins, C-TypeLymphocyte Activation/drug effectsMiceMice, SCIDMultienzyme Complexes/*antagonists & inhibitorsNF-kappa B/metabolismProteasome Endopeptidase ComplexPsoriasis/drug therapy/enzymology/*immunology/pathologyReceptors, Interleukin-2/metabolismSkin Transplantation/immunologySuperantigens/*metabolismT-Lymphocytes/drug effects/*immunologyTransplantation, Heterologous
PMID: 11877475
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ZOLLNER, Thomas Matthias et al. Proteasome inhibition reduces superantigen-mediated T cell activation and the severity of psoriasis in a SCID-hu model. In: Journal of Clinical Investigation, 2002, vol. 109, n° 5, p. 671-679.

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Deposited on : 2013-09-20

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