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Departments of Biochemistry and Molecular Biology (D.R.B., E.T., A.S.H., T.R.Z.) and Pharmacology and Toxicology (R.B.C., N.E.K.), and Center for Integrative Toxicology (D.R.B., R.B.C., N.E.K., T.R.Z.), National Food Safety and Toxicology Center, Michigan State University, East Lansing, Michigan
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 
-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.
Address correspondence to: Dr. Timothy Zacharewski, Michigan State University, Department of Biochemistry and Molecular Biology, 223 Biochemistry Building, Wilson Road, East Lansing, MI 48824-1319. E-mail: tzachare{at}msu.edu
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