Karras J G, Morris D L, Matulka R A, Kramer C M, Holsapple M P
Department of Pharmacology and Toxicology, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298, USA.
Toxicol Appl Pharmacol. 1996 Apr;137(2):275-84. doi: 10.1006/taap.1996.0081.
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.
此前已有研究表明，卤代芳烃环境污染物2,3,7,8-四氯二苯并对二恶英（TCDD）通过直接作用于B淋巴细胞，可抑制对非T细胞依赖性或T细胞依赖性抗原的体液免疫反应。为了更好地理解TCDD诱导的B细胞分化抑制的分子本质，我们使用非T细胞依赖性（针对表面IgM的抗体）和T细胞依赖性[携带CD40配体的活化T辅助（TH）细胞]B细胞成熟的体外模型研究了TCDD的作用。我们在此报告，TCDD可抑制可溶性或不溶性抗IgM加淋巴因子诱导的小鼠B细胞IgM分泌，但不影响活化的T（H）细胞和淋巴因子刺激的IgM分泌。由于发现可溶性或不溶性抗IgM而非固定的活化TH细胞可触发分离的B细胞内离子钙的增加，因此研究了TCDD暴露对B细胞内钙浓度和动员的影响。与内质网钙ATP酶抑制剂毒胡萝卜素相比，毒胡萝卜素可使静息[Ca2+]i立即升高四至五倍，TCDD处理并未使[Ca2+]i迅速增加，但确实导致暴露后18小时基础水平升高至几乎相同的幅度。然而，在有或没有TCDD的情况下，抗IgM诱导的钙瞬变相似。TCDD暴露还导致钙浓度曲线不稳定，在体外和体内处理模式后均观察到基础细胞内钙升高。TCDD和毒胡萝卜素对B细胞对佛波酯加离子霉素的增殖反应的免疫调节活性谱不同，这表明这些化合物释放钙的动力学决定了对反应性B细胞的总体影响。综上所述，数据表明TCDD可提高小鼠B细胞静息细胞内钙水平，并可能选择性抑制与表面Ig相关的钙依赖性信号通路。
