title: Suppression of interleukin-6-induced C-reactive protein expression by FXR agonists.
abstract: C-reactive protein (CRP), a human acute-phase protein, is a risk factor for future cardiovascular events and exerts direct pro-inflammatory and pro-atherogenic properties. The farnesoid X receptor (FXR), a member of the nuclear hormone receptor superfamily, plays an essential role in the regulation of enterohepatic circulation and lipid homeostasis. In this study, we report that two synthetic FXR agonists, WAY-362450 and GW4064, suppressed interleukin-6-induced CRP expression in human Hep3B hepatoma cells. Knockdown of FXR by short interfering RNA attenuated the inhibitory effect of the FXR agonists and also increased the ability of interleukin-6 to induce CRP production. Furthermore, treatment of wild type C57BL/6 mice with the FXR agonist, WAY-362450, attenuated lipopolysaccharide-induced serum amyloid P component and serum amyloid A3 mRNA levels in the liver, whereas no effect was observed in FXR knockout mice. These data provide new evidence for direct anti-inflammatory properties of FXR.
authors.affiliation: Department of Cardiovascular and Metabolic Diseases Research, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. songwen.zhang@boehringer-ingelheim.com
authors.forename: Songwen
authors.initials: S
authors.lastname: Zhang
authors.forename: Qiangyuan
authors.initials: Q
authors.lastname: Liu
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Harnish
mesh_terms: D000210:Acute-Phase Reaction / Q000235:genetics / Q000276:immunology*; D000818:Animals; D002097:C-Reactive Protein / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D034741:RNA, Small Interfering / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002097:C-Reactive Protein; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated