Molecular Mechanism Of TGR5 Inhibition Of Inflammatory Pathway

Inflammation is a common pathological phenomenon,which is related to the occurrence and development of various diseases.Chronic inflammation can develop into a malignant tumor.Therefore,it is very important to study the molecular mechanism of inflammation.Studies have found multiple inflammatory signaling pathways and key signaling factors,and anti-inflammatory drugs based on these important molecules have attracted wide attention.The NF-κB pathway is an important inflammatory pathway.G protein protein bile acid-coupled receptor 5(TGR5)plays an important regulatory role in bile acid metabolism,sugar and energy metabolism,inflammation and cancer.TGR5 can inhibit inflammation through multiple signaling pathways.It has been found that TGR5 can inhibit NF-κB-mediated inflammation by inhibiting IκBαphosphorylation,p65 translocation,and NF-κB binding transcriptional activity.However,the specific molecular mechanism of TGR5-induced inflammation remains to be studied.The cAMP response element binding protein(CREB)is a nuclear regulator and TGR5 regulates the PKA/CREB pathway.B-arrestin2 belongs to the Arrestin family and is a kind of visual inhibitory protein.It is responsible for the regulation of the transduction of G protein-coupled receptor signals,and it loses the ability to bind to other ligands by binding to activated G protein-coupled receptors..Studies have found that activation of TGR5 enhances the interaction between IKBa andβ-arrestin2.TGR5 inhibits the NF-κB pathway by mediating the interaction between I,KBa and β-arrestin2.This experiment further explored the molecular mechanism of TGR5 in the inflammatory pathway,and studied the effect of TGR5 on inflammatory factors and NF-κB pathways in cases where CREB andβ-arrestin2 gene coding were inhibited.TGR5 was activated by TGR5 INT-777 and other activators in mouse macrophages and human gastric cancer cells,respectively,and the expression of CREB and β-arrestin2 genes were silenced by siRNA interference.The results indicate that TGR5 can inhibit p65 and LPS-induced macrophage inflammation and gastritis through the NF-κB pathway.The knockdown of CREB andβ-arrestin2 reduced TGR5’s inhibitory effect on NF-κB pathway and inflammation.