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Received for publication May 19, 2004.
Revised August 25, 2004.
Accepted for publication September 10, 2004.
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 DMSO vehicle using sequence verified cDNA microarrays. One transcript that was significantly induced by TCDD was Socs2, a suppressor of cytokine signaling. Changes in Socs2 mRNA levels paralleled that of cytochrome P450 1a1 (Cyp1a1) with maximal induction of 3-fold observed at 4 hrs as determined by quantitative real-time PCR. Socs2 induction appears B-cell specific as 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 PCB-126, ICZ and BNF. Experiments with cycloheximide and AhR deficient B-cells indicated that Socs2 mRNA induction is a primary effect that is AhR dependent. Western analysis confirmed that Socs2 and Cyp1a1 protein levels were also induced in CH12.LX cells. Promoter analysis revealed the presence of 4 dioxin response elements within 1000 bp 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.
Key words:
Ah receptor, Toxicant-induced gene express
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