Upregulation of intestinal Tumor Growth Factor-β1 is associated with increased intestinal epithelial cell apoptosis in pathogenic simian immunodeficiency virus infection

Abstract

Abstract Mucosal Transforming Growth Factor-β1 (TGF-β1), a pleiotropic, potent immunoregulatory cytokine, demonstrated to manage phosphorylated AKT and IFNγ expressions, are associated with intestinal epithelial cells (iECs) survival in macaque colon explants and suggest a potential role of mucosal TGF-β1 in regulating intestinal homeostasis and iEC integrity. It is important to monitor and further explore the role of mucosal TGF-β1 in HIV/SIV pathogenesis and HIV/SIV enteropathy, which may lead to the development of improved therapeutic strategies to prevent iEC damage and systemic immune activation during acute and chronic infection. Our data showed an increased production of intestinal TGF-β1 in T-, B- and non-T/B cell populations during acute and chronic SIV infection in rhesus macaques, without a change in the expression of TGF-βRII. The increased levels of immunosuppressing TGF-β1 were also associated with increased production of IFNγ, suggest the lack of TGF-β1 mediated anti-inflammatory responses in SIV infection. An appropriate balance between inflammatory and anti-inflammatory cytokine responses are crucial for maintenance of a successful immune responses in HIV infection. TGF-β1 induced immune defects contribute to intestinal inflammation, loss of tight junction protein, and apoptosis by overexpression of SMAD3, and downregulation of inhibitory SMAD7 transcription factors. Together, these results indicate that SMAD mediated pathway play a crucial role in regulating TGF-β1 expression and that was thought to be a key contributor to the dysfunction of CD4+ and CD8+ T-cells, iEC apoptosis and disease progression.