Impact of miR-223-3p and miR-2909 on inflammatory factors IL-6, IL-1ß, and TNF-α, and the TLR4/TLR2/NF-κB/STAT3 signaling pathway induced by lipopolysaccharide in human adipose stem cells

Abstract

MicroRNAs (miRNAs) are small non-coding RNA molecules that play an important role in the regulation of gene expression related to inflammatory responses. Human adipose stem cells are characterized by pluripotent differentiation potential and isolated from adipose tissues. These cells regulate inflammation mainly by interacting with immune cells and affecting the secretion of immune factors; details of this interaction are currently unknown. In the current study, we successfully established an acute inflammation model and a chronic inflammation model involving adipose stem cells. We used high-throughput miRNA microarray analysis to identify miRNAs that were significantly (p < 0.05) differentially expressed during both acute and chronic inflammation. Lipopolysaccharide (LPS) significantly (p < 0.05) reduced the expression of miR-223-3P and miR-2909, while promoting the production of pro-inflammatory cytokines, interleukin (IL) 6, IL-1β, and tumor necrosis factor (TNF)-α via the Toll-like receptor (TLR) 4/TLR2/nuclear factor (NF)-κB/signal transducer and activator of transcription (STAT) 3 signaling pathway in human adipose stem cells. Further, miR-223-3P expression was significantly (p < 0.05) reduced in human adipose stem cells during activation by IL-6 stimulation. The inducible down-regulation of miR-223-3P resulted in the activation of STAT3, which was directly targeted by miR-223-3P. STAT3 directly targeted TLR4 and TLR2, promoting the production of the pro-inflammatory cytokine, IL-6, and formed a positive feedback loop to regulate IL-6 levels. Similarly, TNF-α significantly (p < 0.05) increased the expression of miR-223-3p, with LPS and TLR4/TLR2/NF-κB/STAT3 forming a negative feedback loop to regulate TNF-α levels. In addition, miR-2909, which depends on NF-κB, targeted Krueppel-like factor (KLF) 4 to regulate the levels of pro-inflammatory cytokines, IL-6, IL-1β, and TNF-α. We conclude that miR-223-3p and miR-2909 form a complex regulatory network with pro-inflammatory factors and signaling pathways in adipose stem cells stimulated by LPS. These findings will inform the development of therapies against autoimmune and inflammatory diseases.

Bta-miR-223 Targeting CBLB Contributes to Resistance to Staphylococcus aureus Mastitis Through the PI3K/AKT/NF-κB Pathway

“…In the first 6 h of infection, S. aureus expressed multiple genes related to adhesion, invasion and host defense to escape the immune system (41), which corresponded to the absence of an inflammatory response in the mammary gland. The subsequent increase in the production of TNFA and other pro-inflammatory cytokines between 12 and 24 h of infection increased the expression levels of miR-223 (42), which in turn repressed CBLB expression. However, sustained S. aureus proliferation over the 48 h following infection likely led to a severe inflammatory response that destroyed the mammary gland tissues, and released degrading enzymes or oligonucleotides that degraded bta-miR-223 and reversed the negative regulation of CBLB, eventually increasing its protein levels.…”

MiR‐16, as a potential NF‐κB‐related miRNA, exerts anti‐inflammatory effects on LPS‐induced myocarditis via mediating CD40 expression: A preliminary study

“…It has been shown that the upregulation of gga‐miR‐16‐5p repressed the proliferation of mycoplasma gallisepticum‐infected fibroblast cells by PI3K/Akt/NF‐κB inactivation . As noted by research scholars, IκBα, TNF‐α, and IL‐1β are momentous target genes in the NF‐κB signaling pathway . IκBα, as one of the best‐characterized IκB protein (an inhibitor of NF‐κB), is a multifunctional repressor of NF‐κB, preventing DNA binding and nuclear translocation .…”

Aerobic Exercise Inhibits CUMS-Depressed Mice Hippocampal Inflammatory Response via Activating Hippocampal miR-223/TLR4/MyD88-NF-κB Pathway

“…Reports showed that miR-223 might be a "promoter" that transitions from a pro-inflammatory process to an anti-inflammatory process [37,38]. Studies have found that miR-223 and the inflammatory factors TNF-α, IL-1β, and IL-6 were highly expressed in the lesions of acute spinal cord injury in mice, which reached the maximum peak at 12-24 h after injury [39,40]. There was a positive correlation between the level of miR-223 and the inflammatory factor IL-6 in the acute phase of injury, which indicates that miR-223 might be involved in the regulation of inflammatory factor-mediated spinal inflammatory injury, and its anti-inflammatory effect might be related to the severity and duration of disease damage.…”