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 (TCDD) has previously been shown to directly suppress humoral immunity in mice when administered either in vivo or to isolated low-density B lymphocytes 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, respectively), an early B cell activation event is most likely to be affected by TCDD. Antigen recognition via the surface immunoglobulin (sIg) receptor leads to B cell activation and clonal expansion, priming the cell to secrete specific antibody. The signal transduction events triggered by either antigen or anti-Ig antibodies are similar and relatively well characterized in comparison to other models of B cell activation, such as stimulation by LPS or activated T-helper cell membranes. In order to study the potential effects of TCDD on early B cell activation events, we examined murine low-density B cell responses to activation by anti-IgM in the presence of immunosuppressive concentrations of TCDD. Compared to vehicle controls, TCDD inhibited anti-IgM-stimulated proliferative responses but not Ia expression induced by sIgM ligation. In addition, B cell proliferative responses to the combination of 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 the ionomycin concentration but not the PMA concentration, suggesting that TCDD manifests its anti-proliferative effects on B cells by inhibiting calcium-dependent activation.
Karras
J G
JG
Medical College of Virginia/Virginia Commonwealth University, Richmond 23298-0613.
Holsapple
M P
MP
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000502:physiology; D001402:B-Lymphocytes / Q000187:drug effects*; D002118:Calcium / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005455:Fluorescent Antibody Technique; D007075:Immunoglobulin M / Q000502:physiology; D015759:Ionomycin / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000888:Antibodies, Anti-Idiotypic; D007075:Immunoglobulin M; D000072317:Polychlorinated Dibenzodioxins; C044203:anti-IgM; D015759:Ionomycin; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium