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The steroid and xenobiotic receptor negatively regulates B-1 cell development in the fetal liver.

ABSTRACT: The steroid and xenobiotic receptor (SXR) (also known as pregnane X receptor or PXR) is a broad-specificity nuclear hormone receptor that is well known for its role in drug and xenobiotic metabolism. SXR is activated by a wide variety of endobiotics, dietary compounds, pharmaceuticals, and xenobiotic chemicals. SXR is expressed at its highest levels in the liver and intestine yet is found in lower levels in other tissues, where its roles are less understood. We previously demonstrated that SXR(-/-) mice demonstrate elevated nuclear factor (NF)-?B activity and overexpression of NF-?B target genes and that SXR(-/-) mice develop lymphoma derived from B-1 lymphocytes in an age-dependent manner. In this work, we show that fetal livers in SXR(-/-) mice display elevated expression of NF-?B target genes and possess a significantly larger percentage of B-1 progenitor cells in the fetal liver. Furthermore, in utero activation of SXR in wild-type mice reduces the B-1 progenitor populations in the embryonic liver and reduces the size of the B-1 cell compartment in adult animals that were treated in utero. This suggests that activation of SXR during development may permanently alter the immune system of animals exposed in utero, demonstrating a novel role for SXR in the generation of B-1 cell precursors in the fetal liver. These data support our previous findings that SXR functions as a tumor suppressor in B-1 lymphocytes and establish a unique role for SXR as a modulator of developmental hematopoiesis in the liver.

SUBMITTER: Casey SC

PROVIDER: S-EPMC3355537 | biostudies-other | 2012 Jun

REPOSITORIES: biostudies-other

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The steroid and xenobiotic receptor negatively regulates B-1 cell development in the fetal liver.

Casey Stephanie C SC Blumberg Bruce B

Molecular endocrinology (Baltimore, Md.) 20120411 6

The steroid and xenobiotic receptor (SXR) (also known as pregnane X receptor or PXR) is a broad-specificity nuclear hormone receptor that is well known for its role in drug and xenobiotic metabolism. SXR is activated by a wide variety of endobiotics, dietary compounds, pharmaceuticals, and xenobiotic chemicals. SXR is expressed at its highest levels in the liver and intestine yet is found in lower levels in other tissues, where its roles are less understood. We previously demonstrated that SXR(- ...[more]

PMID: 22496360

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Project description:BackgroundThe steroid and xenobiotic receptor, SXR, is an orphan nuclear receptor that regulates metabolism of diverse dietary, endobiotic, and xenobiotic compounds. SXR is expressed at high levels in the liver and intestine, and at lower levels in breast and other tissues where its function was unknown. Since many breast cancer preventive and therapeutic compounds are SXR activators, we hypothesized that some beneficial effects of these compounds are mediated through SXR.MethodsTo test this hypothesis, we measured proliferation of breast cancer cells in response to SXR activators and evaluated consequent changes in the expression of genes critical for proliferation and cell-cycle control using quantitative RT-PCR and western blotting. Results were confirmed using siRNA-mediated gene knockdown. Statistical analysis was by t-test or ANOVA and a P value < or = 0.05 was considered to be significant.ResultsMany structurally and functionally distinct SXR activators inhibited the proliferation of MCF-7 and ZR-75-1 breast cancer cells by inducing cell cycle arrest at the G1/S phase followed by apoptosis. Decreased growth in response to SXR activation was associated with stabilization of p53 and up-regulation of cell cycle regulatory and pro-apoptotic genes such as p21, PUMA and BAX. These gene expression changes were preceded by an increase in inducible nitric oxide synthase and nitric oxide in these cells. Inhibition of iNOS blocked the induction of p53. p53 knockdown inhibited up-regulation of p21 and BAX. We infer that NO is required for p53 induction and that p53 is required for up-regulation of cell cycle regulatory and apoptotic genes in this system. SXR activator-induced increases in iNOS levels were inhibited by siRNA-mediated knockdown of SXR, indicating that SXR activation is necessary for subsequent regulation of iNOS expression.ConclusionWe conclude that activation of SXR is anti-proliferative in p53 wild type breast cancer cells and that this effect is mechanistically dependent upon the local production of NO and NO-dependent up-regulation of p53. These findings reveal a novel biological function for SXR and suggest that a subset of SXR activators may function as effective therapeutic and chemo-preventative agents for certain types of breast cancers.

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The steroid and xenobiotic receptor negatively regulates B-1 cell development in the fetal liver.

Publications

The steroid and xenobiotic receptor negatively regulates B-1 cell development in the fetal liver.

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