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  • Title: FK506 markedly enhances apoptosis of antigen-stimulated peripheral T cells by down-regulation of Bcl-xL.
    Author: Migita K, Origuchi T, Kawabe Y, Tominaga M, Ida H, Kawakami A, Eguchi K.
    Journal: Transplantation; 1999 Oct 15; 68(7):1018-23. PubMed ID: 10532544.
    Abstract:
    BACKGROUND: FK506 is a clinically effective immunosuppressive agent and promoter of immunologic tolerance. However, limited information is available about the mechanism of FK506-induced immunosuppression. METHODS: In the present study, we investigated the molecular mechanism of FK506-mediated enhancement of apoptosis using in vivo activated T lymphocytes. We examined the effects of FK506 on apoptosis-related proteins in superantigen-stimulated peripheral T cells. RESULTS: Injection of staphylococcal enterotoxin B (SEB) into BALB/c mice resulted in a selective apoptosis of splenic Vbeta8-positive T cells after 48 hr. Injection of FK506 within 36 hr of SEB injection resulted in a marked enhancement of DNA fragmentation of splenic Vbeta8+ T cells. FK506 did not affect the expression of Fas antigen on SEB-activated Vbeta8+ T cells. As Bcl-2-related proteins are involved in apoptotic process, we also evaluated their role by examining the expression of Bcl-2, Bcl-X(L), and Bax on SEB-FK506-treated murine splenic T cells. Although SEB injection slightly increased the expressions of Bcl-2 and Bax on V138+ T cells, FK506 did not modulate Bcl-2 or Bax expression in these cells. In contrast, the expression of Bcl-x(L) on Vgamma8+ T cells, which was markedly induced by SEB, was abrogated by FK506. CONCLUSIONS: Our findings indicate FK506-induced enhancement of apoptosis of activated T cells is mediated by down-regulation of Bcl-X(L) expression on these cells. Our results also suggest that Bcl-x(L) is a critical determinant of apoptosis of activated T cell and may represent a potential target for new therapies designed to achieve immunological tolerance.
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