1. 4-Methylenesterols from Theonella swinhoei sponge are natural pregnane-X-receptor agonists and farnesoid-X-receptor antagonists that modulate innate immunity.
- Author
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De Marino S, Ummarino R, D'Auria MV, Chini MG, Bifulco G, D'Amore C, Renga B, Mencarelli A, Petek S, Fiorucci S, and Zampella A
- Subjects
- Animals, Binding Sites, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes metabolism, Cholesterol analogs & derivatives, Cholesterol chemistry, Cholesterol isolation & purification, Cholesterol pharmacology, Cytokines genetics, Cytokines metabolism, Gene Expression drug effects, Gene Expression Profiling, Hep G2 Cells, Humans, Isomerism, Liver drug effects, Liver metabolism, Liver pathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Models, Molecular, Molecular Structure, Monocytes drug effects, Monocytes metabolism, Pregnane X Receptor, Protein Binding, Protein Structure, Tertiary, Receptors, Cytoplasmic and Nuclear chemistry, Receptors, Cytoplasmic and Nuclear genetics, Receptors, Steroid chemistry, Receptors, Steroid genetics, Reverse Transcriptase Polymerase Chain Reaction, Sterols chemistry, Sterols isolation & purification, T-Lymphocytes, Regulatory drug effects, T-Lymphocytes, Regulatory metabolism, Receptors, Cytoplasmic and Nuclear antagonists & inhibitors, Receptors, Steroid agonists, Sterols pharmacology, Theonella chemistry
- 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., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
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