title: Inhibition of NF-κB by a PXR-dependent pathway mediates counter-regulatory activities of rifaximin on innate immunity in intestinal epithelial cells.
abstract: A dysregulated interaction between intestinal epithelial cells (IEC) and components of innate immunity is a hallmark of inflammatory bowel diseases. Rifaximin is a poorly absorbed oral antimicrobial agent increasingly used in the treatment of inflammatory bowel diseases that has been demonstrated to act as a gut-specific ligand for the human nuclear receptor pregnane-X receptor (PXR). In the present study we investigated, whether activation of PXR in IEC by rifaximin, emanates counter-regulatory signals and modulates the expression of cytokines or chemokines mechanistically involved in dysregulated intestinal immune homeostasis documented in inflammatory bowel diseases. Our results demonstrate that primary IEC express PXR that regulate the pattern of cytokines and chemokines expressed. PXR silencing decreases TGF-β and IP-10 while increases the expression of TNF-α, IL-8, Rantes and increase the production of PGE2. This pattern is further exacerbated by treating anti-PXR siRNA cells with bacterial endotoxin (LPS). Exposure to rifaximin caused a robust attenuation of generation of inflammatory mediators caused by LPS and increased the generation of TGF-β. PXR silencing completely abrogated these anti-inflammatory effects of rifaximin. By Western blot analysis we found that rifaximin abrogates the binding of NF-κB caused by LPS. Finally, exposure of human colon biopsies from inflammatory bowel diseases patients to rifaximin reduced mRNA levels of IL-8, Rantes, MIP-3α and TNFα induced by LPS. Collectively, these data establish that rifaximin exerts counter-regulatory activities at the interface between enteric bacteria and intestinal epithelial cells. The ability of rifaximin to activate PXR contributes to the maintenance of the intestinal immune homeostasis.
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, University of Perugia, Facoltà di Medicina e Chirurgia, Via Gerardo Dottori no 1 S. Andrea delle Fratte, 06132 Perugia, Italy. andrea.mencarelli@unipg.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Mencarelli
authors.forename: Barbara
authors.initials: B
authors.lastname: Renga
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Palladino
authors.forename: D'Amore
authors.initials: D
authors.lastname: Claudio
authors.forename: Patrizia
authors.initials: P
authors.lastname: Ricci
authors.forename: Eleonora
authors.initials: E
authors.lastname: Distrutti
authors.forename: Miriam
authors.initials: M
authors.lastname: Barbanti
authors.forename: Franco
authors.initials: F
authors.lastname: Baldelli
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
mesh_terms: D002460:Cell Line; D018925:Chemokines / Q000096:biosynthesis; D003106:Colon / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004247:DNA / Q000378:metabolism; D053263:Gene Regulatory Networks / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D020868:Gene Silencing; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects* / Q000235:genetics; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012294:Rifamycins / Q000494:pharmacology*; D000078262:Rifaximin; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics / Q000276:immunology
chemical_list: D018925:Chemokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D012294:Rifamycins; D004247:DNA; D000078262:Rifaximin