4-Methylenesterols from Theonella swinhoei sponge are natural pregnane-X-receptor agonists and farnesoid-X-receptor antagonists that modulate innate immunity

被引：42

作者：

De Marino, Simona ^{[1
]}

Ummarino, Raffaella ^{[1
]}

D'Auria, Maria Valeria ^{[1
]}

Chini, Maria Giovanna ^{[2
]}

Bifulco, Giuseppe ^{[2
]}

D'Amore, Claudio ^{[3
]}

Renga, Barbara ^{[3
]}

Mencarelli, Andrea ^{[3
]}

Petek, Sylvain ^{[4
]}

Fiorucci, Stefano ^{[3
]}

Zampella, Angela ^{[1
]}

机构：

[1] Univ Naples Federico II, Dipartimento Chim Sostanze Nat, Via D Montesano 49, I-80131 Naples, Italy

[2] Univ Salerno, Dipartimento Sci Farmaceut & Biomed, I-84084 Fisciano, SA, Italy

[3] Univ Perugia, Dipartimento Med Clin & Sperimentale, Nuova Fac Med & Chirurg, I-06132 Perugia, Italy

[4] Polynesian Res Ctr Isl Biodivers, IRD, F-98713 Papeete, Tahiti, France

来源：

STEROIDS | 2012年 / 77卷 / 05期

关键词：

Marine sponge; Theonella swinhoei; Nuclear receptors; Farnesoid-X-receptor; Pregnane-X-receptor; CHOLESTATIC LIVER-DISEASE; PRIMARY BILIARY-CIRRHOSIS; BILE-ACID; MARINE SPONGE; URSODEOXYCHOLIC ACID; CRYSTAL-STRUCTURE; STEROLS; PXR; RIFAXIMIN; INHIBITION;

D O I：

10.1016/j.steroids.2012.01.006

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. (C) 2012 Elsevier Inc. All rights reserved.

引用

页码：484 / 495

页数：12

共 58 条

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