Inhibition of the proteasome reduces transfer-induced diabetes in nonobese diabetic mice.
Inhibition of the 26S proteasome reduces the severity of several immune-mediated diseases. Here, we report that the proteasome also regulates transfer-induced diabetes in nonobese mice. Treatment of recipient mice with the proteasome inhibitor N(alpha)-benzyloxycarbonyl-l-leucyl-l-leucyl-l-leucinal (MG132) resulted in a 76% reduction in transfer-induced diabetes. The closely related inhibitor carbobenzoxy-l-leucyl-l-leucinal that inhibits calpains but not the proteasome had no protective effect, suggesting that MG132 acted via inhibition of the proteasome. MG132 decreased proliferation of transferred T cells in the pancreatic lymph nodes in vivo and prevented their expansion in a dose-dependent manner in vitro, consistent with a direct effect by MG132 on the T cells. MG132 did not prevent migration of transferred T cells into the islets but reduced the number of mice with severe infiltration. We suggest that MG132 prevents transfer-induced diabetes by directly targeting the autoreactive T cells and lowering their diabetogenic potential.
Petrovic
J
J
Microbiology and Tumor Biology Center, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Hall
H
H
Mehr
R
R
Glas
R
R
Höglund
P
P
D019264:Adoptive Transfer; D000818:Animals; D002455:Cell Division / Q000276:immunology; D003546:Cysteine Endopeptidases / Q000276:immunology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000276:immunology*; D005434:Flow Cytometry; D006029:Glycosuria; D007515:Islets of Langerhans / Q000276:immunology; D007976:Leupeptins / Q000494:pharmacology; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000276:immunology; D046988:Proteasome Endopeptidase Complex; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D009097:Multienzyme Complexes; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde