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dc.contributor.authorJensen, Brenda Aen_US
dc.contributor.authorLeeman, Rebecca Jen_US
dc.contributor.authorSchlezinger, Jennifer Jen_US
dc.contributor.authorSherr, David Hen_US
dc.date.accessioned2011-12-29T22:48:41Z
dc.date.available2011-12-29T22:48:41Z
dc.date.copyright2003
dc.date.issued2003-12-16
dc.identifier.citationJensen, Brenda A, Rebecca J Leeman, Jennifer J Schlezinger, David H Sherr. "Aryl hydrocarbon receptor (AhR) agonists suppress interleukin-6 expression by bone marrow stromal cells: an immunotoxicology study" Environmental Health 2:16. (2003)
dc.identifier.issn1476-069X
dc.identifier.urihttps://hdl.handle.net/2144/2608
dc.description.abstractBACKGROUND: Bone marrow stromal cells produce cytokines required for the normal growth and development of all eight hematopoietic cell lineages. Aberrant cytokine production by stromal cells contributes to blood cell dyscrasias. Consequently, factors that alter stromal cell cytokine production may significantly compromise the development of normal blood cells. We have shown that environmental chemicals, such as aromatic hydrocarbon receptor (AhR) agonists, suppress B lymphopoiesis by modulating bone marrow stromal cell function. Here, we extend these studies to evaluate the potential for two prototypic AhR agonists, 7,12-dimethylbenz [a]anthracene (DMBA) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), to alter stromal cell cytokine responses. METHODS: Bone marrow stromal cells were treated with AhR agonists and bacterial lipopolysaccharide (LPS) to mimic innate inflammatory cytokine responses and to study the effects of AhR ligands on those responses. Steady state cytokine RNA levels were screened by RNAse protection assays (RPA) and quantified by real-time PCR. Cytokine (IL-6) protein production was measured by ELISA. NF-κB EMSAs were used to study IL-6 transcriptional regulation. RESULTS: RPAs indicated that AhR+ bone marrow stromal cells consistently up-regulated genes encoding IL-6 and LIF in response to LPS, presumably through activation of Toll-like receptor 4. Pre-treatment with low doses of DMBA or TCDD selectively abrogated IL-6 gene induction but had no effect on LIF mRNA. Real-time-PCR indicated a significant inhibition of IL-6 mRNA by AhR ligands within 1 hour of LPS challenge which was reflected in a profound down-regulation of IL-6 protein induction, with DMBA and TCDD suppressing IL-6 levels as much as 65% and 88%, respectively. This potent inhibitory effect persisted for at least 72 hours. EMSAs measuring NF-κB binding to IL-6 promoter sequences, an event known to induce IL-6 transcription, indicated a significant decrease in the LPS-mediated induction of DNA-binding RelA/p50 and c-Rel/p50 heterodimers in the presence of DMBA. CONCLUSIONS: Common environmental AhR agonists can suppress the response to bacterial lipopolysaccharide, a model for innate inflammatory responses, through down-regulation of IL-6, a cytokine critical to the growth of several hematopoietic cell subsets, including early B cells. This suppression occurs at least at the level of IL-6 gene transcription and may be regulated by NF-κB.en_US
dc.description.sponsorshipNational Institutes of Health (RO1-ES06086, Superfund Basic Research Grant 1P42ES-07381, PO1 HL 68705)en_US
dc.language.isoen
dc.publisherBioMed Centralen_US
dc.rightsCopyright 2003 Jensen et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.en_US
dc.titleAryl Hydrocarbon Receptor (AhR) Agonists Suppress Interleukin-6 Expression by Bone Marrow Stromal Cells: An Immunotoxicology Studyen_US
dc.typeArticleen_US
dc.identifier.doi10.1186/1476-069X-2-16
dc.identifier.pmid14678569
dc.identifier.pmcid317352


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