Suppression of adult T cell leukemia-derived factor/human thioredoxin induction by FK506 and cyclosporin A: a new mechanism of immune modulation via redox control.
Adult T cell leukemia-derived factor (ADF), which is identical to a disulfide reducing enzyme human thioredoxin (TRX), is produced and released by activated or virus-infected lymphocytes. Here we report that, in peripheral blood mononuclear cells (PBMC) stimulated with phytohemagglutinin (PHA), ADF/TRX mRNA was induced within 8 h after stimulation as detected by in situ hybridization study. To analyze the mechanism of ADF/TRX induction during T cell activation, the effects of immunosuppressants including FK506, rapamycin (Rap) and cyclosporin A (CsA) on ADF/TRX expression were investigated by immunoblot analysis. ADF/TRX induction in PBMC by PHA, Con A or OKT3 mAb was almost completely suppressed by FK506. Whereas CsA also inhibited ADF/TRX expression in OKT3 mAb-stimulated PBMC, Rap failed to affect it in spite of exhibiting growth inhibition. In addition, exogenous IL-2 could not increase ADF/TRX production in FK506-treated PBMC or in PHA blasts. These results indicate that ADF/TRX induction in T cell activation depends on calcineurin-dependent events in the early phase and that IL-2 production is not directly involved in ADF/TRX induction. Furthermore, when recombinant ADF (rADF) was added to a culture of PBMC 1 h before the addition of PHA and FK506, the action of FK506 was partially reversed as determined by [3H]thymidine incorporation and viable cell counts. These results suggest that ADF/TRX produced and released from PBMC may be a crucial event in lymphocyte activation, and that FK506 and CsA may exert the immune suppression partly through inhibiting the induction of the endogenous reducing factor ADF/TRX.
Furuke
K
K
Institute for Virus Research, Kyoto University, Japan.
Nakamura
H
H
Hori
T
T
Iwata
S
S
Maekawa
N
N
Inamoto
T
T
Yamaoka
Y
Y
Yodoi
J
J
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D010084:Oxidation-Reduction / Q000187:drug effects; D011090:Polyenes / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D011994:Recombinant Proteins / Q000494:pharmacology; D020123:Sirolimus; D016559:Tacrolimus / Q000494:pharmacology*; D013879:Thioredoxins / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics
D000276:Adjuvants, Immunologic; D016207:Cytokines; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D009363:Neoplasm Proteins; D011090:Polyenes; D012333:RNA, Messenger; D011994:Recombinant Proteins; C055533:adult T cell leukemia-derived factor; D013879:Thioredoxins; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus