Glucocorticoid activates STAT3 and NF-κB synergistically with inflammatory cytokines to enhance the anti-inflammatory factor TSG6 expression in mesenchymal stem/stromal cells.
Peiqing HuangRongrong SunChenchang XuZixuan JiangMuqiu ZuoYinghong LiRui LiuPixia GongYuyi HanJiankai FangPeishan LiChangshun ShaoYufang ShiPublished in: Cell death & disease (2024)
Glucocorticoid (GC) is essential for maintaining immune homeostasis. While GC is known to regulate the expression of genes related to inflammation in immune cells, the effects of GC, especially in the presence of inflammation, on non-immune cells remain largely unexplored. In particular, the impact of GC on inflammatory cytokine-induced immune modulatory responses of tissue stromal cells is unknown, though it has been widely used to modulate tissue injuries. Here we found that GC could enhance the expression of TSG6, a vital tissue repair effector molecule, in IFNγ and TNFα treated human umbilical cord (UC)-MSCs. NF-κB activation was found to be required for GC-augmented TSG6 upregulation. STAT3, but not STAT1, was also found to be required for the TSG6 upregulation in MSCs exposed to IFNγ, TNFα and GC. Moreover, the phosphorylation (activation) of STAT3 was attenuated when NF-κB was knocked down. Importantly, human UC-MSCs pretreated with a cocktail containing GC, IFNγ, and TNFα could significantly enhance the therapeutic effect of human UC-MSCs in an acute lung injury mouse model, as reflected by reduced infiltration of immune cells and down-regulation of iNOS in macrophages in the lung. Together, the findings reveal a novel link between GR, NF-κB and STAT3 in regulating the immunomodulatory and regenerative properties of MSCs, providing novel information for the understanding and treatment of inflammatory conditions.
Keyphrases
- mesenchymal stem cells
- umbilical cord
- poor prognosis
- oxidative stress
- signaling pathway
- cell proliferation
- gas chromatography
- lps induced
- endothelial cells
- rheumatoid arthritis
- dendritic cells
- pi k akt
- immune response
- mouse model
- stem cells
- bone marrow
- induced pluripotent stem cells
- nuclear factor
- pluripotent stem cells
- mass spectrometry
- high glucose
- binding protein
- long non coding rna
- healthcare
- gene expression
- tandem mass spectrometry
- toll like receptor
- lipopolysaccharide induced
- dna methylation
- smoking cessation
- high resolution
- transcription factor
- combination therapy
- virtual reality