FK506 markedly enhances apoptosis of antigen-stimulated peripheral T cells by down-regulation of Bcl-xL.
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.
Migita
K
K
The First Department of Internal Medicine, Nagasaki University School of Medicine, Japan. e.g.uchi@net.nagasaki-u.ac.jp
Origuchi
T
T
Kawabe
Y
Y
Tominaga
M
M
Ida
H
H
Kawakami
A
A
Eguchi
K
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053938:DNA Fragmentation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004768:Enterotoxins / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D013211:Staphylococcus aureus / Q000276:immunology; D018089:Superantigens / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology*; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D004768:Enterotoxins; D007166:Immunosuppressive Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D018089:Superantigens; D051020:bcl-X Protein; C031818:enterotoxin B, staphylococcal; D016559:Tacrolimus