The immunosuppressive capacity of mesenchymal stem cells (MSCs) is dependent on the 'license' of several proinflammatory factors to express immunosuppressive factors such as programmed cell death 1 ligand 1 (PD-L1), which determines the clinical therapeutic efficacy of MSCs for inflammatory or immune diseases. In MSCs, interferon-gamma (IFN-γ) is a key inducer of PD-L1 expression, which is synergistically enhanced by tumor necrosis factor-alpha (TNF-α); however, the underlying mechanism is unclear.
Molecular mechanism of interferon-gamma and tumor necrosis factor-alpha synergistically upregulated expression of programmed cell death protein 1 ligand in human umbilical-cord-mesenchymal stem cells to inhibit T cells. IFN-γ: Interferon-gamma; PD-L1: Programmed cell death protein 1 ligand 1; TNF-α: Tumor necrosis factor-alpha; hUC-MSCs: Human umbilical-cord-mesenchymal stem cells; IRF1: Interferon regulatory factor 1.
For this study, researchers assessed PD-L1 expression in human umbilical-cord-derived MSCs induced by IFN-γ and TNF-α, alone or in combination. Additionally, they performed signal pathway inhibitor experiments as well as RNA interference experiments to elucidate theThey used luciferase reporter gene experiments to verify the binding sites of the transcription factors of each signal transduction pathway to the targeted gene promoters.
Although TNF-α alone did not induce PD-L1 expression in hUC-MSCs, the addition of TNF-α significantly enhanced IFN-γ-induced JAK/STAT1/IRF1 activation. TNF-α up-regulated IFN-γ receptor expression through activation of the nuclear factor kappa-B signaling pathway, which significantly enhanced IFN-γ signaling.
Overall, the results suggest that IFN-γ and TNF-α enhance both the immunosuppressive ability of hUC-MSCs and their efficacy inZhuo Chen et al, Interferon-gamma and tumor necrosis factor-alpha synergistically enhance the immunosuppressive capacity of human umbilical-cord-derived mesenchymal stem cells by increasing PD-L1 expression,: retrieved 28 August 2023 from https://phys.org/news/2023-08-immunosuppressive-capacity-human-umbilical-cordderived-mesenchymal-stem.
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