2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elevates basal B-cell intracellular calcium concentration and suppresses surface Ig- but not CD40-induced antibody secretion.
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 using in vitro models 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 T(H)-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+]i of up to four- to fivefold, TCDD treatment did not produce a rapid increase in [Ca2+]i but 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 both in vitro and in vivo treatment 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.
Karras
J G
JG
Department of Pharmacology and Toxicology, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298, USA.
Morris
D L
DL
Matulka
R A
RA
Kramer
C M
CM
Holsapple
M P
MP
D000818:Animals; D000906:Antibodies / Q000378:metabolism; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007424:Intracellular Fluid / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008222:Lymphokines / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D012995:Solubility; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D013729:Terpenes / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019284:Thapsigargin
D000906:Antibodies; D000888:Antibodies, Anti-Idiotypic; D019013:CD40 Antigens; D004791:Enzyme Inhibitors; D007476:Ionophores; D008070:Lipopolysaccharides; D008222:Lymphokines; D000072317:Polychlorinated Dibenzodioxins; D011947:Receptors, Antigen, B-Cell; D013729:Terpenes; C044203:anti-IgM; D015759:Ionomycin; D019284:Thapsigargin; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium