B-1 cell lymphoma in mice lacking the steroid and xenobiotic receptor, SXR
Stephanie C Casey1, Edward L Nelson, Gina M Turco
1Developmental and Cell Biology, University of California, Irvine, California 92697-2300, USA.
Abstract:
The steroid and xenobiotic receptor (SXR) is a broad-specificity nuclear hormone receptor that is highly expressed in the liver and intestine, where its primary function is to regulate drug and xenobiotic metabolism. SXR is expressed at lower levels in other tissues, where little is known about its physiological functions. We previously linked SXR with immunity and inflammation by showing that SXR antagonizes the activity of nuclear factor (NF)-κB in vitro and in vivo. SXR(-/-) mice demonstrate aberrantly high NF-κB activity and overexpression of NF-κB target genes. Here we show that SXR(-/-) mice develop B cell lymphoma in an age-dependent manner. SXR(-/-) mice develop multiple hyperplastic lymphoid foci composed of B-1a cells in the intestine, spleen, lymph nodes, peritoneal cavity, and blood. In all circumstances, these lymphocytes possess cell surface and molecular characteristics of either chronic lymphocytic leukemia or non-Hodgkin's lymphoma originating from B-1 lymphocytes. These results demonstrate a novel and unsuspected role for SXR signaling in the B-1 cell compartment, establish SXR as a tumor suppressor in B-1 cells, and may provide a link between metabolism of xenobiotic compounds and lymphomagenesis.
Insights
The steroid and xenobiotic receptor (SXR) acts as a tumor suppressor in B-1 cells. Loss of SXR in mice leads to B cell lymphoma, suggesting a link between xenobiotic metabolism and cancer.
Area of Science:
- Immunology
- Molecular Biology
- Cancer Research
Background:
- The steroid and xenobiotic receptor (SXR) is a nuclear receptor primarily regulating xenobiotic metabolism in the liver and intestine.
- SXR's role in other tissues, particularly in immunity and inflammation, is less understood.
- Previous studies linked SXR to the antagonism of nuclear factor-kappa B (NF-κB) signaling.
Purpose of the Study:
- To investigate the physiological functions of SXR in B-1 cells.
- To determine the role of SXR in lymphomagenesis.
- To explore the connection between SXR signaling, xenobiotic metabolism, and cancer development.
Main Methods:
- Analysis of SXR knockout (SXR(-/-)) mice.
- Assessment of NF-κB activity and target gene expression in SXR(-/-) mice.
- Histopathological examination of lymphoid tissues and characterization of lymphocyte populations.
Main Results:
- SXR(-/-) mice exhibited age-dependent development of B cell lymphoma.
- Hyperplastic lymphoid foci composed of B-1a cells were observed in multiple organs of SXR(-/-) mice.
- These B-1 lymphocytes displayed characteristics of chronic lymphocytic leukemia or non-Hodgkin's lymphoma.
Conclusions:
- SXR plays a critical role in suppressing tumor formation in the B-1 cell compartment.
- SXR deficiency leads to aberrant NF-κB activity and promotes B cell lymphomagenesis.
- These findings highlight a novel function of SXR in immunity and suggest a link between xenobiotic metabolism and cancer.
