Abstract
In the present study we provide evidence that solomonsterol A, a selective pregnane X receptor (PXR) agonist isolated from the marine sponge Theonella swinhoei, exerts anti-inflammatory activity and attenuates systemic inflammation and immune dysfunction in a mouse model of rheumatoid arthritis. Solomonsterol A was effective in protecting against the development of arthritis induced by injecting transgenic mice harboring a humanized PXR, with anti-collagen antibodies (CAIA) with beneficial effects on joint histopathology and local inflammatory response reducing the expression of inflammatory markers (TNFα, IFNγ and IL-17 and chemokines MIP1α and RANTES) in draining lymph nodes. Solomonsterol A rescued mice from systemic inflammation were assessed by measuring arthritis score, CRP and cytokines in the blood. In summary, the present study provides a molecular basis for the regulation of systemic local and systemic immunity by PXR agonists.
Highlights
A class of ligand activated regulatory factors termed nuclear receptors (NRs) has been identified as critical biological guidelines for many biological processes including fine-tuning regulation of innate and adaptive immunity and offers the prospect of multiple targeting
We investigated whether solomonsterol A interacts with a panel of nuclear receptors including pregnane X receptor (PXR), FXR, LXRα, GR and PPARγ in a transactivaton assay in HepG2 cells
Plasma samples collected from control, collagen antibody induced-arthritis group (CAIA) and CAIA-solomonsterol A groups were used to measure the levels of C-Reactive Protein (CRP), Tumor Necrosis Factor α (TNF-α), Interferon γ (INF-γ), Interleukin 17 (IL-17), Interleukin 10 (IL-10), Monocyte Chemoattractant Protein 1 (MCP-1)
Summary
A class of ligand activated regulatory factors termed nuclear receptors (NRs) has been identified as critical biological guidelines for many biological processes including fine-tuning regulation of innate and adaptive immunity and offers the prospect of multiple targeting. In addition to its role in regulating xenobiotic metabolism, PXR exerts immunomodulatory and anti-inflammatory activities by inhibiting the function of NF-κB [5,9,10], a transcription factor which regulates the production of many genes associated with both innate and adaptive immunity such as cytokines, chemokines, adhesion proteins and stress response genes. Theonella swinhoei, was found to be the first example of a marine potent human PXR agonist boosting the receptor activity by 4−5 fold in transactivation assays [19] and stimulating the expression of PXR target genes CYP3A4 and MDR1 in a human hepatocyte cell line. Results of present study suggest that targeting PXR might be of relevance in treating systemic inflammation
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