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

Int Immunol. 1995 Jun;7(6):985-93. doi: 10.1093/intimm/7.6.985.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / pharmacology*
  • Cyclosporine / pharmacology*
  • Cytokines / biosynthesis
  • Cytokines / drug effects*
  • Cytokines / genetics
  • Growth Inhibitors / pharmacology
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Interleukin-2 / pharmacology
  • Leukocytes, Mononuclear / drug effects
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / drug effects*
  • Neoplasm Proteins / genetics
  • Oxidation-Reduction / drug effects
  • Polyenes / pharmacology
  • RNA, Messenger / analysis
  • Recombinant Proteins / pharmacology
  • Sirolimus
  • Tacrolimus / pharmacology*
  • Thioredoxins / biosynthesis
  • Thioredoxins / drug effects*
  • Thioredoxins / genetics


  • Adjuvants, Immunologic
  • Cytokines
  • Growth Inhibitors
  • Immunosuppressive Agents
  • Interleukin-2
  • Neoplasm Proteins
  • Polyenes
  • RNA, Messenger
  • Recombinant Proteins
  • adult T cell leukemia-derived factor
  • Thioredoxins
  • Cyclosporine
  • Sirolimus
  • Tacrolimus