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

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• 作者：Simona De Marino^a ; Raffaella Ummarino^a ; Maria Valeria D&rsquo ; Auria^a ; Maria Giovanna Chini^b ; Giuseppe Bifulco^b ; Claudio D&rsquo ; Amore^c ; Barbara Renga^c ; Andrea Mencarelli^c ; Sylvain Petek^d ; Stefano Fiorucci^c ; ¹ ; Angela Zampella^a ; ¹ ; ^{angela.zampella@unina.it}
• 关键词：Marine sponge ; Theonella swinhoei ; Nuclear receptors ; Farnesoid-X-receptor ; Pregnane-X-receptor
• 刊名：Steroids
• 出版年：2012
• 期刊代码：142_0039128x
• 类别：bio
• 出版时间：April, 2012
• 卷：77
• 期：5
• 页码：484-495
• 文件大小：1212 K

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.