TY - JOUR T1 - 2,3,7,8-Tetrachlorodibenzo-<em>p</em>-dioxin Induces Suppressor of Cytokine Signaling 2 in Murine B Cells JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1662 LP - 1670 DO - 10.1124/mol.104.002915 VL - 66 IS - 6 AU - Darrell R. Boverhof AU - Elaine Tam AU - Allison S. Harney AU - Robert B. Crawford AU - Norbert E. Kaminski AU - Timothy R. Zacharewski Y1 - 2004/12/01 UR - http://molpharm.aspetjournals.org/content/66/6/1662.abstract N2 - 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 β-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. ER -