Transforming growth factor β stimulates the human immunodeficiency virus 1 enhancer and requires NF-κB activity

Transforming growth factor beta (TGF-beta) is the prototype of a large superfamily of signaling molecules involved in the regulation of cell growth and differentiation. In certain patients infected with human immunodeficiency virus type 1 (HIV-1), increased levels of TGF-beta promoted the production of virus and also impaired the host immune system. In an effort to understand the signaling events linking TGF-beta action and HIV production, we show here that TGF-beta can stimulate transcription from the HIV-1 long terminal repeat (LTR) promoter through NF-kappa B binding sites in both HaCaT and 300.19 pre-B cells. When introduced into a minimal promoter, NF-kappa B binding sites supported nearly 30-fold activation from the luciferase reporter upon TGF-beta treatment, Electrophoretic mobility shift assay indicated that a major factor binding to the NF-KB site is the p50-p65 heterodimeric NF-kappa B in HaCaT cells. Coexpression of Gal4-p65 chimeric proteins supported TGF-beta ligand-dependent gene expression from a luciferase reporter gene driven by Gal4 DNA binding sites, NF-kappa B activity present in HaCaT cells was not affected by TGF-beta treatment as judged by the unchanged DNA binding activity and concentrations of p50 and p65 proteins, Consistently, steady-state levels of I kappa B gamma and I kappa B beta proteins were not changed by TGF-beta treatment, Our results demonstrate that TGF-beta is able to stimulate transcription from the HIV-1 LTR promoter by activating NF-kappa B through a mechanism distinct from the classic NF-kappa B activation mechanism involving the degradation of I kappa B proteins.