INHIBITION OF CALCIUM-DEPENDENT B-CELL ACTIVATION BY 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCD D) has previously been shown to directly suppress humoral immunity in mice when administered either in vivo or to isolated low-density B lym phocytes in culture. Because TCDD-mediated suppression of the antibody forming cell response to both LPS and SRBC was found to require early xenobiotic exposure (i.e., within 3 and 24 hr of antigen addition, re spectively), an early B cell activation event is most likely to be aff ected by TCDD. Antigen recognition via the surface immunoglobulin (sIg ) receptor leads to B cell activation and clonal expansion, priming th e cell to secrete specific antibody. The signal transduction events tr iggered by either antigen or anti-Ig antibodies are similar and relati vely well characterized in comparison to other models of B cell activa tion, such as stimulation by LPS or activated T-helper cell membranes. In order to study the potential effects of TCDD on early B cell activ ation events, we examined murine low-density B cell responses to activ ation by anti-IgM in the presence of immunosuppressive concentrations of TCDD. Compared to vehicle controls, TCDD inhibited anti-IgM-stimula ted proliferative responses but not Ia expression induced by sIgM liga tion. In addition, B cell proliferative responses to the combination o f PMA and ionomycin were suppressed by up to 50% of control levels at 30 nM TCDD, indicating that TCDD may disrupt signaling pathways distal to phospholipase C. The magnitude of TCDD-induced suppression of the PMA plus ionomycin induced proliferative response was dependent upon t he ionomycin concentration but not the PMA concentration, suggesting t hat TCDD manifests its antiproliferative effects on B cells by inhibit ing calcium-dependent activation. (C) 1994 Academic Press, Inc.