Abstract
Humoral immune responses to either T-independent or T-dependent antigens have previously been shown to be suppressed by the halogenated aromatic hydrocarbon environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) through direct action on B-lymphocytes. To better understand the molecular nature of the TCDD-induced suppression of B-cell differentiation, we studied the effects of TCDD usingin vitromodels of T-independent (antibody directed against surface IgM) and T-dependent [activated T-helper (TH)-cells bearing CD40 ligand] B-cell maturation. We report here that TCDD suppresses murine B-cell IgM secretion induced by either soluble or insolubilized anti-IgM plus lymphokines but does not affect IgM secretion stimulated by activated TH-cells and lymphokines. Because soluble or insolubilized anti-IgM but not fixed, activated TH-cells was found to trigger increases in intracellular ionized calcium in isolated B-cells, the effect of TCDD exposure on B-cell intracellular calcium concentration and mobilization was examined. In comparison to the endoplasmic reticulum calcium ATPase inhibitor thapsigargin, which induces an immediate rise in resting [Ca2+]iof up to four- to fivefold, TCDD treatment did not produce a rapid increase in [Ca2+]ibut did result in an elevation of basal levels of nearly the same magnitude 18 hr postexposure. However, anti-IgM-induced calcium transients were similar in the presence or absence of TCDD. TCDD exposure also produced instability of the calcium concentration curve, with the observed elevation of basal intracellular calcium occurring after bothin vitroandin vivotreatment paradigms. The immunomodulatory profiles of activity of TCDD and thapsigargin on the B-cell proliferative response to PMA plus ionomycin differ, suggesting that the kinetics of calcium release by these compounds dictates the overall effect on the responding B-cell. Taken together, the data indicate that TCDD elevates resting intracellular calcium levels in murine B-cells and may selectively inhibit calcium-dependent signaling pathways linked to surface Ig.
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