Proteasome regulation of activation-induced T cell death

AUTOR(ES)

Cui, Haili

FONTE

The National Academy of Sciences of the USA

RESUMO

Lactacystin, a microbial metabolite that inhibits protease activity only in the proteasome, was used to study the role of the proteasome in the activation-induced cell death (AICD) of T cells. Lactacystin induces DNA fragmentation and apoptosis in a T cell hybridoma (DO.11.10) in a dose-dependent manner. Between 1 and 10 μM, the mildly cytotoxic lactacystin inhibited the AICD of DO.11.10 cells cultured in anti-CD3-coated wells. Degradation of IκBβ and the translocation of the NF-κB (p50/RelA) into the nucleus, which occurred at 1.5 hr after anti-CD3 activation, were inhibited by lactacystin. Lactacystin did not inhibit the expression of nuclear transcription factor Oct-1. The activation-induced expression of the immediate–early gene, Nur77, and the T cell death genes, CD95 (Fas) and CD95 ligand (FasL), were inhibited. Functional expression of FasL cytotoxicity and the increase of cell surface Fas were also inhibited. Lactacystin must be added within 2 hr of activation to efficiently block AICD. In addition, lactacystin failed to inhibit the killing of DO.11.10 by FasL-expressing allo-specific cytotoxic effector cells. These observations strongly suggest a direct link between the proteasome-dependent degradation of IκBβ and the AICD that occurs through activation of the FasL gene and up-regulation of the Fas gene.

Documentos Relacionados

• Differential ability of T cell subsets to undergo activation-induced cell death
• FK506 augments activation-induced programmed cell death of T lymphocytes in vivo.
• Activation-induced T-cell death is cell cycle dependent and regulated by cyclin B.
• Ouabain exacerbates activation-induced cell death in human peripheral blood lymphocytes
• Lymphocyte Apoptosis during Classical Swine Fever: Implication of Activation-Induced Cell Death