title: G-protein-coupled bile acid receptor 1 (GPBAR1, TGR5) agonists reduce the production of proinflammatory cytokines and stabilize the alternative macrophage phenotype.
abstract: GPBAR1 (also known as TGR5) is a G-protein-coupled receptor (GPCR) that triggers intracellular signals upon ligation by various bile acids. The receptor has been studied mainly for its function in energy expenditure and glucose homeostasis, and there is little information on the role of GPBAR1 in the context of inflammation. After a high-throughput screening campaign, we identified isonicotinamides exemplified by compound 3 as nonsteroidal GPBAR1 agonists. We optimized this series to potent derivatives that are active on both human and murine GPBAR1. These agonists inhibited the secretion of the proinflammatory cytokines TNF-α and IL-12 but not the antiinflammatory IL-10 in primary human monocytes. These effects translate in vivo, as compound 15 inhibits LPS induced TNF-α and IL-12 release in mice. The response was GPBAR1 dependent, as demonstrated using knockout mice. Furthermore, agonism of GPBAR1 stabilized the phenotype of the alternative, noninflammatory, M2-like type cells during differentiation of monocytes into macrophages. Overall, our results illustrate an important regulatory role for GPBAR1 agonists as controllers of inflammation.
authors.affiliation: Global Discovery Chemistry, ‡Autoimmunity, Transplantation and Inflammation, and §Center for Proteomic Chemistry, Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Klemens
authors.initials: K
authors.lastname: Högenauer
authors.forename: Luca
authors.initials: L
authors.lastname: Arista
authors.forename: Niko
authors.initials: N
authors.lastname: Schmiedeberg
authors.forename: Gudrun
authors.initials: G
authors.lastname: Werner
authors.forename: Herbert
authors.initials: H
authors.lastname: Jaksche
authors.forename: Rochdi
authors.initials: R
authors.lastname: Bouhelal
authors.forename: Deborah G
authors.initials: DG
authors.lastname: Nguyen
authors.forename: B Ganesh
authors.initials: BG
authors.lastname: Bhat
authors.forename: Layla
authors.initials: L
authors.lastname: Raad
authors.forename: Celine
authors.initials: C
authors.lastname: Rauld
authors.forename: José M
authors.initials: JM
authors.lastname: Carballido
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism*; D019169:Jurkat Cells; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; C513561:Gpbar1 protein, mouse; D007211:Indoles; D008070:Lipopolysaccharides; C000595868:N-(4-fluoro-2-methylphenyl)-3-methyl-N-((2-methyl-1H-indol-4-yl)methyl)isonicotinamide; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D009536:Niacinamide; D000242:Cyclic AMP; D002118:Calcium