Activation of the aryl hydrocarbon receptor/transcription factor and bone marrow stromal cell-dependent preB cell apoptosis

In the absence of known endogenous ligands, investigators have exploited ubiquitous environmental pollutants, including polycyclic aromatic hydrocarbons, to gain insight into the physiologic functions of the aryl hydrocarbon (dioxin) receptor/ transcription factor (AhR). AhR ligands induce cell transformation and steroid-like immunosuppression, suggesting a role for the AhR in regulation of cell growth and/or function. However, mechanisms through which the AhR influences cells in general and lymphocytes in particular remain unresolved. A murine model of B cell development was created to: 1) examine a role for the AhR in immunosuppression; 2) define mechanisms of AhR ligand immunosuppression; 3) characterize AhR expression in preB cells, in bone marrow stromal cells that support preB cells, or in primary bone marrow B cells; and 4) determine if AhR ligands suppress lymphopoiesis by acting directly on preB cells or indirectly via the microenvironment, as represented by bone marrow stromal cells. Results indicate that: 1) low doses (greater than or equal to 10(-8) M) of the prototypic AhR ligand, 7,12-dimethylbenz[a]anthracene (DMBA), induce preB cell apoptosis in 12 to 24 h; 2) alpha-naphthoflavone, an AhR and cytochrome P-450 inhibitor, blocks DMBA-induced apoptosis; 3) AhR mRNA and functional AhR protein are expressed at high levels in bone marrow stromal cells (little or no AhR is present in preB cell lines), and 4) preB cells maintained in rlL-7 do not undergo DMBA-induced apoptosis unless cultured with stromal cells. Results underscore the regulatory role played by bone marrow stromal cells in lymphopoiesis and support the hypothesis that the AhR effects immunosuppression by inducing stromal cells to deliver a death signal to lymphocytes.