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 exploit ed ubiquitous environmental pollutants, including polycyclic aromatic hydrocarbons, to gain insight into the physiologic functions of the ar yl hydrocarbon (dioxin) receptor/ transcription factor (AhR). AhR liga nds induce cell transformation and steroid-like immunosuppression, sug gesting a role for the AhR in regulation of cell growth and/or functio n. However, mechanisms through which the AhR influences cells in gener al and lymphocytes in particular remain unresolved. A murine model of B cell development was created to: 1) examine a role for the AhR in im munosuppression; 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 b y bone marrow stromal cells. Results indicate that: 1) low doses (grea ter than or equal to 10(-8) M) of the prototypic AhR ligand, 7,12-dime thylbenz[a]anthracene (DMBA), induce preB cell apoptosis in 12 to 24 h ; 2) alpha-naphthoflavone, an AhR and cytochrome P-450 inhibitor, bloc ks DMBA-induced apoptosis; 3) AhR mRNA and functional AhR protein are expressed at high levels in bone marrow stromal cells (little or no Ah R is present in preB cell lines), and 4) preB cells maintained in rlL- 7 do not undergo DMBA-induced apoptosis unless cultured with stromal c ells. Results underscore the regulatory role played by bone marrow str omal cells in lymphopoiesis and support the hypothesis that the AhR ef fects immunosuppression by inducing stromal cells to deliver a death s ignal to lymphocytes.