Abstract
Transforming growth factor-β signaling (TGF-β) maintains a balanced physiological function including cell growth, differentiation, and proliferation and regulation of immune system by modulating either SMAD2/3 and SMAD7 (SMAD-dependent) or SMAD-independent signaling pathways under normal conditions. Increased production of TGF-β promotes immunosuppression in Human Immunodeficiency Virus (HIV)/Simian Immunodeficiency Virus (SIV) infection. However, the cellular source and downstream events of increased TGF-β production that attributes to its pathological manifestations remain unknown. Here, we have shown increased production of TGF-β in a majority of intestinal CD3−CD20−CD68+ cells from acute and chronically SIV infected rhesus macaques, which negatively correlated with the frequency of jejunum CD4+ T cells. No significant changes in intestinal TGF-β receptor II expression were observed but increased production of the pSMAD2/3 protein and SMAD3 gene expression in jejunum tissues that were accompanied by a downregulation of SMAD7 protein and gene expression. Enhanced TGF-β production by intestinal CD3−CD20−CD68+ cells and increased TGF-β/SMAD-dependent signaling might be due to a disruption of a negative feedback loop mediated by SMAD7. This suggests that SIV infection impacts the SMAD-dependent signaling pathway of TGF-β and provides a potential framework for further study to understand the role of viral factor(s) in modulating TGF-β production and downregulating SMAD7 expression in SIV. Regulation of mucosal TGF-β expression by therapeutic TGF-β blockers may help to create effective antiviral mucosal immune responses.
Highlights
Transforming growth factor-β1 (TGF-β1) is an immunoregulatory cytokine that is produced by a variety of immune cells including lymphocytes, macrophages, dendritic cells, and intestinal epithelial cells
Highlighting its role in maintaining intestinal homeostasis and epithelial cell integrity, we have recently demonstrated that Transforming growth factor-β signaling (TGF-β) promotes epithelial cell survival in rhesus macaque (RhM) colon explants via increased pAKT and decreased IFNγ expression [1]
The SMAD2-SMAD3 complex binds with SMAD4 and translocates to the nucleus to act as a transcription factor, regulating the expression of different target genes including IL-1β, TNF-α, MCP-1 genes, Chitinase-3-like protein 1 genes, Bcl-2, Caspase-3 genes and Granzyme A, Granzyme B, IFNγ, and FasL genes [9,10]
Summary
Transforming growth factor-β1 (TGF-β1) is an immunoregulatory cytokine that is produced by a variety of immune cells including lymphocytes, macrophages, dendritic cells, and intestinal epithelial cells. Highlighting its role in maintaining intestinal homeostasis and epithelial cell integrity, we have recently demonstrated that TGF-β promotes epithelial cell survival in rhesus macaque (RhM) colon explants via increased pAKT and decreased IFNγ expression [1] Since it has both adverse and favorable physiological activities on diverse cellular processes, stringent regulation of its signaling pathways is necessary to ensure its proper and balanced physiological functions [3,4]. The SMAD-independent pathway is mediated via various protein kinases of mitogen-activate protein kinase (MAPK) family members like extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT), and Rho-like GTPase These are activated by ligand-occupied receptors to repress, modulate, or activate several downstream cellular responses including TGF-βmediated apoptosis, extracellular matrix production, and differentiation [15]. We present evidence that in a RhM SIV infection model, increased production of intestinal TGF-β was not accompanied by increased TGF-β receptor expression; rather, we found increased phosphorylated SMAD2/3 (pSMAD2/3) regulatory protein production and SMAD3 gene expression, along with significantly decreased protein and gene expression of the inhibitory SMAD7 during SIV infection
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