Aryl Hydrocarbon Receptor-Dependent Suppression by 2,3,7,8-Tetrachlorodibenzo-p-dioxin of IgM Secretion in Activated B Cells

Abstract

The immune system has been identified as a sensitive target for the toxic effects produced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Furthermore, the B cell has been identified as a sensitive cellular target of TCDD by previous cell-type fractionation studies from this laboratory. The mechanism responsible for the immunotoxic effects produced by TCDD is unclear; however, many of the biological effects of TCDD are thought to be mediated by the aryl hydrocarbon receptor (AhR). Here, we describe two B cell lines that differ considerably in their expression of the AhR and in their sensitivity to TCDD. Our results demonstrated a marked expression of the AhR protein in the CH12.LX B cell line but not in the BCL-1 B cell line. Transcripts for the AhR were not detected by reverse transcriptase-polymerase chain reaction in the BCL-1 cells. The AhR nuclear translocator (ARNT) protein was highly expressed in both cell lines. In addition, the AhR and ARNT are functional in CH12.LX cells as demonstrated by TCDD-induced CYP1A1 induction. TCDD did not induce CYP1A1 in BCL-1 cells. Furthermore, TCDD treatment resulted in suppression of lipopolysaccharide (LPS)-induced IgM secretion in CH12.LX cells. Conversely, TCDD-induced inhibition of IgM secretion was not demonstrated in LPS-stimulated BCL-1 cells, implicating a role for the AhR in the inhibition of B cell effector function. LPS-induced differentiation of the CH12.LX cells also resulted in a marked induction of Ahr expression which was not induced in LPS-stimulated BCL-1 cells. These studies have implicated the AhR as a critical factor in TCDD-induced inhibition of IgM secretion and have demonstrated an induction of AhR gene and protein expression after B cell activation.

Dioxin-mediated tumor progression through activation of mitochondria-to-nucleus stress signaling

“…The fact that TCDD-induced expression of nuclear target genes observed in the present work was highly sensitive to FK506 treatment and CnA mRNA silencing suggests that CnA is involved in these transcriptional responses and in the activation of NF-B. In keeping with this possibility it has been reported that TCDD activates NF-B by AhR-independent mechanisms (40,41).…”

Immunologic biomarkers in relation to exposure markers of PCBs and dioxins in Flemish adolescents (Belgium).

“…In experimental systems (animal and in vitro experiments), PCB/dioxin exposure leads to suppression of humoral and cell-mediated immunity and has direct effects on hematopoietic stem cells and B-cell or T-cell differentiation (8,11,36,37). However, the underlying mechanisms for these effects have not been fully elucidated.…”

The aryl hydrocarbon receptor constitutively represses c-myc transcription in human mammary tumor cells

“…The AhR can both induce (Matikainen et al, 2001(Matikainen et al, , 2002Nebert et al, 1991) and suppress gene transcription (Sulentic et al, 1998;Wang et al, 1999Wang et al, , 2001). Therefore, a human c-myc promoter-reporter construct (pGL3-c-myc) was used to determine if constitutive AhR binding to the c-myc promoter effects an increase or decrease of c-myc levels.…”

“…AhR-dependent upregulation of these enzymes results in increased metabolism of some AhR ligands such as PAH and the production of carcinogenic intermediates (Buters et al, 1999;Dertinger et al, 2001). In other cases, activation of the AhR results in transcriptional inhibition of genes such as those encoding the immunoglobulin heavy-chain (Sulentic et al, 2000) and estrogen-inducible p27, cathepsin D, and pS2 (Safe et al, 1998;Porter et al, 2001).…”