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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: 2,3,7,8-Tetrachlorodibenzo-p-dioxin induces suppressor of cytokine signaling 2 in murine B cells.

Authors: Boverhof, Darrell R; Tam, Elaine; Harney, Allison S; Crawford, Robert B; Kaminski, Norbert E; Zacharewski, Timothy R

Published In Mol Pharmacol, (2004 Dec)

Abstract: The B cell, a major component of humoral immunity, is a sensitive target for the immunotoxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), possibly by rendering cells less responsive to antigenic or mitogenic stimulation. Potential mechanisms of TCDD action on B cells were examined in murine B cell lymphoma cells (CH12.LX) treated with 3 nM TCDD or dimethyl sulfoxide vehicle using sequence-verified cDNA microarrays. One transcript that was significantly induced by TCDD was suppressor of cytokine signaling 2 (Socs2). Changes in Socs2 mRNA levels paralleled that of Cyp1a1 with a maximal 3-fold induction observed at 4 h, as determined by quantitative real-time polymerase chain reaction. Socs2 induction seems B cell-specific, because no induction was observed in TCDD-responsive mouse hepatoma cells or human breast cancer cells. TCDD-mediated induction of Socs2 mRNA was dose-dependent and exhibited the characteristic structure-activity relationships observed for the aryl hydrocarbon receptor (AhR) ligands 3,3',4,4',5-pentachlorobiphenyl (PCB-126), indolo[3,2-b]-carbazole, and beta-naphthoflavone. Experiments with cycloheximide and AhR-deficient B cells indicated that Socs2 mRNA induction is a primary effect that is AhR-dependent. Western blot analysis confirmed that Socs2 and Cyp1a1 protein levels were also induced in CH12.LX cells. Promoter analysis revealed the presence of four dioxin-response elements within 1000 base pairs upstream of the Socs2 transcriptional start site, and a reporter gene regulated by the Socs2 promoter was inducible by TCDD. Promoter activity was also dependent on a functional AhR signaling pathway. These results indicate that Socs2 is a primary TCDD-inducible gene that may represent a novel mechanism by which TCDD elicits its immunosuppressive effects.

PubMed ID: 15371557 Exiting the NIEHS site

MeSH Terms: Animals; B-Lymphocytes/drug effects; B-Lymphocytes/physiology*; Base Sequence; Cell Line, Tumor; Cytochrome P-450 CYP1A1/genetics; DNA Primers; DNA-Binding Proteins/genetics*; Gene Expression Regulation/drug effects; Lymphoma, B-Cell; Mice; Oligonucleotide Array Sequence Analysis; Polychlorinated Dibenzodioxins/pharmacology*; Repressor Proteins/genetics*; Signal Transduction; Suppressor of Cytokine Signaling Proteins; Trans-Activators/genetics*

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