INTERLEUKIN-7 UP-REGULATES THE INTERLEUKIN-2-GENE EXPRESSION IN ACTIVATED HUMAN T-LYMPHOCYTES AT THE TRANSCRIPTIONAL LEVEL BY ENHANCING THEDNA-BINDING ACTIVITIES OF BOTH NUCLEAR FACTOR OF ACTIVATED T-CELLS AND ACTIVATOR PROTEIN-1

In the present report, we studied the role of the stromal-derived cyto kine interleukin-7 (IL-7) in the IL-2-gene regulation in activated T l ymphocytes. Production of IL-2 requires the formation of transcription factors involved in the IL-2-gene regulation, T-cell receptor (TCR)/C D3 engagement results in the activation of nuclear factor of activated T cells (NFAT), activator protein-1 (AP-1), and nuclear factor kappa B (NF kappa B), whereas the CD28 responsive complex (CD28RC) is activa ted in response to the CD28 signal. Costimulation of phytohemagglutini n/anti-CD28 activated T lymphocytes with IL-7 induces a fivefold enhan ced IL-2-mRNA accumulation and a 2.5-fold enhanced protein secretion. The IL-2-gene transcription rate is increased 3.4-fold, indicating tha t the effect of IL-7 is in part mediated at the transcriptional level. The molecular mechanisms underlying the IL-7 effect involve the upreg ulation of the DNA binding activity of NFAT (60%) and AP-1 (120%), wit hout affecting the activities of NF kappa B and CD28RC, which was conf irmed by transfection assays, We also show that the IL-7-induced enhan cement of the AP-1-DNA binding activity is not cyclosporin A-sensitive , Since AP-1 is part of the NFAT complex, we conclude that the IL-7-si gnaling pathway is involved in the activation of the fos and jun prote ins of which AP-1 consists. (C) 1997 by The American Society of Hemato logy.