title: Activation of the bile acid receptor TGR5 enhances LPS-induced inflammatory responses in a human monocytic cell line.
abstract: BACKGROUND
  Bile acids are recognized as signaling molecules, mediating their effects both through the cell surface receptor TGR5 and the nuclear receptor FXR. After a meal, approximately 95% of the bile acids are transported from terminal ileum and back to the liver via the portal vein, resulting in postprandial elevations of bile acids in blood. During the digestion of fat, components from the microbiota, including LPS, are thought to reach the circulation where it may lead to inflammatory responses after binding TLR4 immune cells. Both LPS and bile acids are present in blood after a high-fat meal; we therefore wanted to study consequences of a possible interplay between TGR5 and TLR4 in human monocytes.
  
  
  METHODS
  The monocytic cell line U937 stably transfected with the NF-κB reporter plasmid 3x-κB-luc was used as a model system to study the effects of TGR5 and TLR4. Activation of MAP kinases was studied to reveal functional consequences of triggering TGR5 in U937 cells. Effects of TGR5 and TLR4 activation were monitored using NF-κB luciferase assay and by quantification of the pro-inflammatory cytokines IL-6 and IL-8 using ELISA.
  
  
  RESULTS
  In this study, results show that triggering TGR5 with the specific agonist betulinic acid (BA), and the bile acids CDCA or DCA, activated both the main MAP kinases ERK1/2, p38 and JNK, and the NF-κB signaling pathway. We further demonstrated that co-triggering of TLR4 and TGR5 enhanced the activation of NF-κB and the release of inflammatory cytokines in a synergistic manner compared to triggering of TLR4 alone.
  
  
  CONCLUSIONS
  Thus, two different and simultaneous events associated with the digestive process coordinately affect the function of human monocytes and contribute to enhanced inflammation. Because elevated levels of circulatory LPS may contribute to the development of insulin resistance, the results from this study suggest that bile acids through the activation of TGR5 may have a role in the development of insulin resistance as well.
authors.affiliation: a Department of Chemistry , Biotechnology and Food Science, Norwegian University of Life Sciences , Ås , Norway and.
authors.forename: Kaia
authors.initials: K
authors.lastname: Mobraten
authors.affiliation: a Department of Chemistry , Biotechnology and Food Science, Norwegian University of Life Sciences , Ås , Norway and.
authors.forename: Tarjei
authors.initials: T
authors.lastname: Haugbro
authors.affiliation: a Department of Chemistry , Biotechnology and Food Science, Norwegian University of Life Sciences , Ås , Norway and.
authors.forename: Ellen
authors.initials: E
authors.lastname: Karlstrom
authors.affiliation: a Department of Chemistry , Biotechnology and Food Science, Norwegian University of Life Sciences , Ås , Norway and.|b Quality and Research Department , Ostfold Hospital Trust , Fredrikstad , Norway.
authors.forename: Charlotte R
authors.initials: CR
authors.lastname: Kleiveland
authors.affiliation: a Department of Chemistry , Biotechnology and Food Science, Norwegian University of Life Sciences , Ås , Norway and.
authors.forename: Tor
authors.initials: T
authors.lastname: Lea
mesh_terms: D002460:Cell Line; D006801:Humans; D007155:Immunologic Factors / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology*; D008070:Lipopolysaccharides; D009000:Monocytes / Q000276:immunology* / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology*
chemical_list: C473772:GPBAR1 protein, human; D007155:Immunologic Factors; D008070:Lipopolysaccharides; D043562:Receptors, G-Protein-Coupled; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4
keywords: Cytokines; G-protein coupled receptor; NFκBs and inflammation; lipopolysaccharide