Interferon-alpha activates multiple STAT proteins and upregulates proliferation-associated IL-2R alpha, c-myc, and pim-1 genes in human T cells

Interferon-alpha (IFN-alpha) is a pleiotropic cytokine that has antiviral, antiproliferative, and immunoregulatory functions. There is increasing evid ence that IFN-alpha has an important role in T-cell biology. We have analyz ed the expression of IL-2R alpha, c-myc, and pim-1 genes in anti-CD3-activa ted human T lymphocytes. The induction of these genes is associated with in terleukin-2 (IL-2)-induced T-cell proliferation. Treatment of T lymphocytes with IFN-alpha, IL-2, IL-12, and IL-15 upregulated IL-2R alpha, c-myc, and pim-1 gene expression. IFN-alpha also sensitized T cells to IL-2-induced p roliferation, further suggesting that IFN-alpha may be involved in the regu lation of T-cell mitogenesis. When we analyzed the nature of STAT proteins capable of binding to IL-2R alpha, pim-1, and IRF-1 GAS elements after cyto kine stimulation, we observed IFN-alpha-induced binding of STAT1, STAT3, an d STAT4, but not STAT5 to all of these elements. Yet, IFN-alpha was able to activate binding of STAT5 to the high-affinity IFP53 GAS site. IFN-alpha e nhanced tyrosine phosphorylation of STAT1. STAT3, STAT4, STAT5a, and STAT5b . IL-12 induced STAT4 and IL-2 and IL-15 induced STAT5 binding to the GAS e lements. Taken together, our results suggest that IFN-alpha, IL-2, IL-12, a nd IL-15 have overlapping activities on human T cells. These findings thus emphasize the importance of IFN-alpha as a T-cell regulatory cytokine. (C) 1999 by The American Society of Hematology.