title: 4-Methylenesterols from Theonella swinhoei sponge are natural pregnane-X-receptor agonists and farnesoid-X-receptor antagonists that modulate innate immunity.
abstract: We report the isolation and the structural elucidation of a family of polyhydroxylated steroids from the marine sponge Theonella swinhoei. Decodification of interactions of these family with nuclear receptors shows that these steroids are potent agonists of human pregnane-X-receptor (PXR) and antagonists of human farnesoid-X-receptor (FXR) with the putative binding mode to nuclear receptors (NRs) obtained through docking experiments. By using monocytes isolated from transgenic mice harboring hPXR, we demonstrated that swinhosterol B counter-regulates induction of pro-inflammatory cytokines in a PXR-dependent manner. Exposure of CD4(+) T cells to swinhosterol B upregulates the expression of IL-10 causing a shift toward a T cells regulatory phenotype in a PXR dependent manner. These results pave the way to development of a dual PXR agonist/FXR antagonist with a robust immunomodulatory activity and endowed with the ability to modulate the expression of bile acid-regulated genes in the liver.
authors.affiliation: Dipartimento di Chimica delle Sostanze Naturali, Università di Napoli "Federico II", Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: De Marino
authors.forename: Raffaella
authors.initials: R
authors.lastname: Ummarino
authors.forename: Maria Valeria
authors.initials: MV
authors.lastname: D'Auria
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Chini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bifulco
authors.forename: Claudio
authors.initials: C
authors.lastname: D'Amore
authors.forename: Barbara
authors.initials: B
authors.lastname: Renga
authors.forename: Andrea
authors.initials: A
authors.lastname: Mencarelli
authors.forename: Sylvain
authors.initials: S
authors.lastname: Petek
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
authors.forename: Angela
authors.initials: A
authors.lastname: Zampella
mesh_terms: D000818:Animals; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000031:analogs & derivatives / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D056945:Hep G2 Cells; D006801:Humans; D007536:Isomerism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D000077297:Pregnane X Receptor; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D011987:Receptors, Steroid / Q000819:agonists* / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013261:Sterols / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism; D047232:Theonella / Q000737:chemistry*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002784:Cholesterol; D016207:Cytokines; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013261:Sterols; D000099150:Receptor, Farnesoid X-Activated; C098158:conicasterol