title: Bile acids PKA-dependently induce a switch of the IL-10/IL-12 ratio and reduce proinflammatory capability of human macrophages.
abstract: That cholestatic conditions are accompanied by an enhanced susceptibility to bacterial infection in human and animal models is a known phenomenon. This correlates with the observation that bile acids have suppressive effects on cells of innate and adaptive immunity. The present study provides evidence that in human macrophages, bile acids inhibit the LPS-induced expression of proinflammatory cytokines without affecting the expression of the anti-inflammatory cytokine IL-10. This results in a macrophage phenotype that is characterized by an increased IL-10/IL-12 ratio. Correspondingly, bile acids suppress basal phagocytic activity of human macrophages. These effects of bile acids can be mimicked by cAMP, which is presumably induced TGR5-dependently. The data provided further suggest that in primary human macrophages, modulation of the macrophage response toward LPS by bile acids involves activation of CREB, disturbed nuclear translocation of NF-κB, and PKA-dependent enhancement of LPS-induced cFos expression. The increase in cFos expression is paralleled by an enhanced formation of a protein complex comprising cFos and the p65 subunit of NF-κB. In summary, the data provided suggest that in human macrophages, bile acids induce an anti-inflammatory phenotype characterized by an increased IL-10/IL-12 ratio via activation of PKA and thereby, prevent their activation as classically activated macrophages. This bile acid-induced modulation of macrophage function may also be responsible for the experimentally and clinically observed anti-inflammatory and immunosuppressive effects of bile acids.
authors.affiliation: 1.Hepatology und Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, D-40225 Düsseldorf, Germany. dirk.graf@med.uni-duesseldorf.de.
authors.forename: Katrin
authors.initials: K
authors.lastname: Haselow
authors.forename: Johannes G
authors.initials: JG
authors.lastname: Bode
authors.forename: Marianne
authors.initials: M
authors.lastname: Wammers
authors.forename: Christian
authors.initials: C
authors.lastname: Ehlting
authors.forename: Verena
authors.initials: V
authors.lastname: Keitel
authors.forename: Laura
authors.initials: L
authors.lastname: Kleinebrecht
authors.forename: Anna-Kathrin
authors.initials: AK
authors.lastname: Schupp
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
authors.forename: Dirk
authors.initials: D
authors.lastname: Graf
mesh_terms: D001647:Bile Acids and Salts / Q000276:immunology* / Q000378:metabolism; D000242:Cyclic AMP / Q000235:genetics / Q000276:immunology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000276:immunology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000276:immunology* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology* / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology*; D008264:Macrophages / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000276:immunology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000276:immunology; D051996:Transcription Factor RelA / Q000235:genetics / Q000276:immunology
chemical_list: D001647:Bile Acids and Salts; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C473772:GPBAR1 protein, human; C508609:IL10 protein, human; D008070:Lipopolysaccharides; C498143:RELA protein, human; D043562:Receptors, G-Protein-Coupled; D051996:Transcription Factor RelA; D016753:Interleukin-10; D018664:Interleukin-12; D000242:Cyclic AMP; D051076:Proto-Oncogene Proteins c-fyn; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: LPS; TGR5; TLC; TLR; cytokines