Proteasome inhibition reduces superantigen-mediated T cell activation and the severity of psoriasis in a SCID-hu model.
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.
Zollner
Thomas M
TM
Department of Dermatology, J.W. Goethe University of Frankfurt, Frankfurt, Germany. Thomas.Zollner@Schering.de
Podda
Maurizio
M
Pien
Christine
C
Elliott
Peter J
PJ
Kaufmann
Roland
R
Boehncke
Wolf-Henning
WH
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D001427:Bacterial Toxins; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004768:Enterotoxins / Q000276:immunology; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D016513:Mice, SCID; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D016328:NF-kappa B / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011565:Psoriasis / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D016038:Skin Transplantation / Q000276:immunology; D018089:Superantigens / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014183:Transplantation, Heterologous; D000099192:CD69 Antigens
D000111:Acetylcysteine; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D001427:Bacterial Toxins; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors; D004247:DNA; D004768:Enterotoxins; D006684:HLA-DR Antigens; D037181:Lectins, C-Type; D009097:Multienzyme Complexes; D016328:NF-kappa B; D046988:Proteasome Endopeptidase Complex; D015375:Receptors, Interleukin-2; D018089:Superantigens; D000099192:CD69 Antigens; C411422:PS519; C030107:enterotoxin F, Staphylococcal