الملخص
Taurochenodeoxycholic acid (TCDCA) is one of the main effective components of bile acid, playing critical roles in apoptosis and immune responses through the TGR5 receptor. In this study, we reveal the interaction between TCDCA and TGR5 receptor in TGR5-knockdown H1299 cells and the regulation of inflammation via the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP response element binding (CREB) signal pathway in NR8383 macrophages. In TGR5-knockdown H1299 cells, TCDCA significantly activated cAMP level via TGR5 receptor, indicating TCDCA can bind to TGR5; in NR8383 macrophages TCDCA increased cAMP content compared to treatment with the adenylate cyclase (AC) inhibitor SQ22536. Moreover, activated cAMP can significantly enhance gene expression and protein levels of its downstream proteins PKA and CREB compared with groups of inhibitors. Additionally, TCDCA decreased tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, IL-8 and IL-12 through nuclear factor kappa light chain enhancer of activated B cells (NF-κB) activity. PKA and CREB are primary regulators of anti-inflammatory and immune response. Our results thus demonstrate TCDCA plays an essential anti-inflammatory role via the signaling pathway of cAMP-PKA-CREB induced by TGR5 receptor.
الموضوعات
Animals , Humans , Rats , Cell Line , Cyclic AMP/metabolism , Cyclic AMP Response Element-Binding Protein/metabolism , Cyclic AMP-Dependent Protein Kinases/metabolism , Cytokines/metabolism , Inflammation , Macrophages , Receptors, G-Protein-Coupled/metabolism , Signal Transduction/drug effects , Taurochenodeoxycholic Acid/pharmacologyالملخص
GPCBAR1, also known as TGR5 receptor, is one member of the GPCRs family. TGR5, a pattern recognition receptor located on cell membrane, is widely expressed in human beings and animals, playing numerous significant roles in anti-inflammation and immune regulation, energy metabolism, glucose metabolism and anti-cancer. Many signaling pathways are induced by TGR5 upon activated. AKT, NF-kB, ERK, STAT3, cAMP signaling pathways, methods and results of TGR5-mediated signaling pathways and t(ie development of new drugs via TGR5-mediated signaling pathways were reviewed in this paper.