title: The oxysterol receptor LXRβ protects against DSS- and TNBS-induced colitis in mice.
abstract: We examined the function of the oxysterol receptors (LXRs) in inflammatory bowel disease (IBD) through studying dextran sodium sulfate (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice and by elucidating molecular mechanisms underlying their anti-inflammatory action. We observed that Lxr-deficient mice are more susceptible to colitis. Clinical indicators of colitis including weight loss, diarrhea and blood in feces appeared earlier and were more severe in Lxr-deficient mice and particularly LXRβ protected against symptoms of colitis. Addition of an LXR agonist led to faster recovery and increased survival. In contrast, Lxr-deficient mice showed slower recovery and decreased survival. In Lxr-deficient mice, inflammatory cytokines and chemokines were increased together with increased infiltration of immune cells in the colon epithelium. Activation of LXRs strongly suppressed expression of inflammatory mediators including TNFα. While LXRα had anti-inflammatory effects in CD11b(+) immune cell populations, LXRβ in addition had anti-inflammatory effects in colon epithelial cells. Lack of LXRβ also induced CD4(+)/CD3(+) immune cell recruitment to the inflamed colon. Expression of both LXRA and LXRB was significantly suppressed in inflamed colon from subjects with IBD compared with non-inflamed colon. Taken together, our observations suggest that the LXRs could provide interesting targets to reduce the inflammatory responses in IBD.
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Jakobsson
authors.affiliation: Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: L-L
authors.initials: LL
authors.lastname: Vedin
authors.affiliation: Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Hassan
authors.affiliation: Institute of Cardiometabolism and Nutrition, INSERM, Université Pierre et Marie Curie-Paris 6, Cordeliers Research Center, Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Venteclef
authors.affiliation: Finnish Institute of Occupational Health, Helsinki, Finland.
authors.forename: D
authors.initials: D
authors.lastname: Greco
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: D'Amato
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Treuter
authors.affiliation: 1] Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden [2] Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA.
authors.forename: J-Å
authors.initials: JÅ
authors.lastname: Gustafsson
authors.affiliation: Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: K R
authors.initials: KR
authors.lastname: Steffensen
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D003106:Colon / Q000276:immunology* / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity*; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D000071518:Liver X Receptors; D051379:Mice; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000276:immunology*; D014301:Trinitrobenzenes / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D014301:Trinitrobenzenes; D014409:Tumor Necrosis Factor-alpha; C029222:sym-trinitrobenzene; D016264:Dextran Sulfate