GLI2 regulates TGF-β1 in human CD4+ T cells: implications in cancer and HIV pathogenesis

• Published in: PloS one Vol. 7; no. 7; p. e40874
• Main Authors: Furler, Robert L, Uittenbogaart, Christel H
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 31.07.2012; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; AIDS; Binding Sites; Biology; Cancer; CD25 antigen; CD4 antigen; CD4-Positive T-Lymphocytes - metabolism; Cells, Cultured; Gene Expression Regulation; Gene regulation; Genes, Reporter; Hedgehog protein; HIV; HIV Infections - immunology; HIV Infections - metabolism; Human immunodeficiency virus; Humans; Immune response; Immunoregulation; Infections; Kinases; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Kruppel-Like Transcription Factors - physiology; Luciferases, Firefly - biosynthesis; Luciferases, Firefly - genetics; Lymphocytes; Lymphocytes T; Medicine; Neoplasms - immunology; Neoplasms - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Nuclear Proteins - physiology; Pathogenesis; Promoter Regions, Genetic; Protein Binding; Rodents; Sequence Analysis, DNA; tat Gene Products, Human Immunodeficiency Virus - metabolism; Transcription, Genetic; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; Zinc Finger Protein Gli2; Los Angeles California; United States > US; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0040874

Elevated levels of the immunoregulatory cytokine TGF-β1 in cancer and HIV infection have been linked to the suppression of protective immune responses. The transcriptional regulation of TGF-β1 is complex and still not completely understood. We report here for the first time that the transcription factor GLI2 regulates the expression of TGF-β1 in human CD4(+) T cells. In silico screening revealed five novel putative GLI binding sites in the human TGF-β1 promoter. At least two of these sites within the human TGF-β1 promoter are regulated by the GLI2 activator as knockdown of GLI2 in regulatory CD4(+)CD25(hi) T cells, high producers of TGF-β1, significantly decreased TGF-β1 transcription. Additionally, naïve CD4(+) T cells, low producers of TGF-β1, increased their basal level of TGF-β1 mRNA following lentiviral infection with GLI2. The transcriptional regulation of TGF-β1 by GLI2 is a new extension to Sonic Hedgehog (SHH) and TGF-β1 cross-regulation and may provide insight into the detrimental elevation of TGF-β1 leading to pathogenesis in cancer and HIV infection.