Transcriptional control of human T‐BET expression: The role of Sp1

Abstract

Murine T‐bet (T‐box expressed in T cells) is a master regulator of IFN‐γ gene expression in NK and T cells. T‐bet also plays a critical role in autoimmunity, asthma and other diseases. However, cis elements or trans factors responsible for regulating T‐bet expression remain largely unknown. Here, we report on our discovery of six Sp1‐binding sites within the proximal human T‐BET promoter that are highly conserved among mammalian species. Electrophoretic mobility shift assays demonstrate a physical association between Sp1 and the proximal T‐BET promoter with a direct dose response between Sp1 expression and T‐BET promoter activity. Ectopic overexpression of Sp1 also enhanced T‐BET expression and cytokine‐induced IFN‐γ secretion in NK cells and T cells. Mithramycin A, which blocks the binding of Sp1 to the T‐BET promoter, diminished both T‐BET expression and IFN‐γ protein production in monokine‐stimulated primary human NK cells. Collectively, our results suggest that Sp1 is a positive transcriptional regulator of T‐BET. As T‐BET and IFN‐γ are critically important in inflammation, infection, and cancer, targeting Sp1, possibly with mithramycin A, may be useful for preventing and/or treating diseases associated with aberrant T‐BET or IFN‐γ expression.