IFN-τ mediated miR-26a targeting PTEN to activate PI3K/AKT signalling to alleviate the inflammatory damage of bEECs

Abstract

Endometritis is the failure of embryo implantation and an important cause of infertility in dairy cows. IFN-τ is a type I interferon unique to ruminants. In regulating the process of inflammatory response, IFN-τ can be expressed through MicroRNAs (miRNAs) to regulate the process of inflammation. However, IFN-τ regulates lipopolysaccharide (LPS)-induced inflammatory injury of bEECs through the highly conserved miR-26a in mammals, and the mechanism remains unclear. Bovine endometrial epithelial cells (bEECs)were isolated and cultured to establish an inflammatory injury model. RT–qPCR and ELISA were used to detect the secretion of inflammatory factors. Dual-luciferase assays and target gene silencing assays determine the regulatory role of miRNAs. The target protein was detected by immunofluorescence and western blotting. This study showed that the expression of miR-26a was significantly down-regulated in mouse endometrium inflammatory injury tissue and LPS stimulated bEECs; and IFN-τ reversed the expression of miR-26a. The study also showed that the overexpression of miR-26a significantly inhibited the secretion of pro-inflammatory cytokines IL-1β, IL-6 and TNF-α. In addition, studies have shown that miR-26a inhibits its translation by targeting PTEN 3′-UTR, which in turn activates the Phosphatidylinositide 3-kinases/protein kinase B (PI3K/AKT) pathway, so that nuclear factor kappa-B (NF-κB) signaling is inhibited. In summary, the results of this study further confirm that IFN-τ as an anti-inflammatory agent can up-regulate the expression of miR-26a and target the PTEN gene to inhibit the inflammatory damage of bEECs.

Molecular Mechanisms Associated with the Development of the Metritis Complex in Dairy Cattle

“…Moreover, in the current study, 9 of the 20 genes found flanking the top significant SNPs were discovered to be linked to the phosphatidylinositol-3-kinase/protein kinase B (PI 3 K/Akt) pathway. The PI 3 K/Akt pathway has been recently discussed in terms of its essential role in signal transduction, cell proliferation, apoptosis, and autophagy and its correspondence to pathogenesis within bovine endometrial epithelial cells [64]. The activated pathway phosphorylates Akt downstream, and active Akt has been found to deter the fusion of the autophagosome to the lysosome, allowing for the survival of pathogenic materials and promoting infection [65,66].…”

“…These secondary pathways work to inhibit, activate, and compete with the activity of PI 3 K/Akt and, consequently, regulate autophagosome elongation, maturation, and termination and the autophagy process [70][71][72]. The PI 3 K/Akt pathway was considerably discussed for its role in bovine physiology including oocyte competence, immune responsiveness, milk fat synthesis, bacterial resistance, vascular homeostasis, and angiogenesis [64,[73][74][75][76]. Our study reports the link between the development of uterine infections in dairy cattle and the PI 3 K/Akt pathway, considering its major role in pathogenesis and the immune response.…”