title: Ursodeoxycholic acid inhibits TNFα-induced IL-8 release from monocytes.
abstract: Monocytes are critical to the pathogenesis of inflammatory bowel disease (IBD) as they infiltrate the mucosa and release cytokines that drive the inflammatory response. Ursodeoxycholic acid (UDCA), a naturally occurring bile acid with anti-inflammatory actions, has been proposed as a potential new therapy for IBD. However, its effects on monocyte function are not yet known. Primary monocytes from healthy volunteers or cultured U937 monocytes were treated with either the proinflammatory cytokine, TNFα (5 ng/ml) or the bacterial endotoxin, lipopolysaccharide (LPS; 1 μg/ml) for 24 h, in the absence or presence of UDCA (25-100 μM). IL-8 release into the supernatant was measured by ELISA. mRNA levels were quantified by qPCR and changes in cell signaling proteins were determined by Western blotting. Toxicity was assessed by measuring lactate dehydrogenase (LDH) release. UDCA treatment significantly attenuated TNFα-, but not LPS-driven, release of IL-8 from both primary and cultured monocytes. UDCA inhibition of TNFα-driven responses was associated with reduced IL-8 mRNA expression. Both TNFα and LPS stimulated NFκB activation in monocytes, while IL-8 release in response to both cytokines was attenuated by an NFκB inhibitor, BMS-345541. Interestingly, UDCA inhibited TNFα-, but not LPS-stimulated, NFκB activation. Finally, TNFα, but not LPS, induced phosphorylation of TNF receptor associated factor (TRAF2), while UDCA cotreatment attenuated this response. We conclude that UDCA specifically inhibits TNFα-induced IL-8 release from monocytes by inhibiting TRAF2 activation. Since such actions would serve to dampen mucosal immune responses in vivo, our data support the therapeutic potential of UDCA for IBD.
authors.affiliation: Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education & Research Centre, Beaumont Hospital, Dublin, Ireland; and.
authors.forename: Aoife M
authors.initials: AM
authors.lastname: O'Dwyer
authors.affiliation: Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education & Research Centre, Beaumont Hospital, Dublin, Ireland; and.
authors.forename: Natalia K
authors.initials: NK
authors.lastname: Lajczak
authors.affiliation: Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education & Research Centre, Beaumont Hospital, Dublin, Ireland; and.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Keyes
authors.affiliation: Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education & Research Centre, Beaumont Hospital, Dublin, Ireland; and.
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Ward
authors.affiliation: Department of Medicine, Royal College of Surgeons in Ireland, Education & Research Centre, Beaumont Hospital, Dublin, Ireland.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Greene
authors.affiliation: Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education & Research Centre, Beaumont Hospital, Dublin, Ireland; and skeely@rcsi.ie.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Keely
mesh_terms: D005786:Gene Expression Regulation; D006801:Humans; D018928:Immunity, Mucosal / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D020298:U937 Cells; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
chemical_list: C508606:CXCL8 protein, human; D007166:Immunosuppressive Agents; D016209:Interleukin-8; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D014580:Ursodeoxycholic Acid
keywords: colitis; cytokine; innate immunity; monocyte; ursodeoxycholic acid