ACUTE INFLAMMATORY RESPONSE TO SHEEP RED-BLOOD-CELL CHALLENGE IN MICE TREATED WITH 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) - PHENOTYPIC AND FUNCTIONAL-ANALYSIS OF PERITONEAL-EXUDATE CELLS
ACUTE INFLAMMATORY RESPONSE TO SHEEP RED-BLOOD-CELL CHALLENGE IN MICE TREATED WITH 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) - PHENOTYPIC AND FUNCTIONAL-ANALYSIS OF PERITONEAL-EXUDATE CELLS
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DOI：
10.1006/taap.1993.1066
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发表时间：
1993-04-01
影响因子：
3.8
通讯作者：
OUGHTON, JA
中科院分区：
文献类型：
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作者：
KERKVLIET, NI;OUGHTON, JA
TCDD是一种广泛存在的环境污染物，由于其对实验动物具有公认的免疫毒性，因此对人类健康具有广泛的影响。抑制小鼠对异种红细胞的抗体反应已被证明是TCDD免疫毒性最敏感的检测方法之一。然而，抑制免疫功能的细胞机制尚未完全阐明。本研究比较了C57B1/6小鼠单次灌胃0和5μg TCDD/kg后，对绵羊红细胞注射后小鼠腹腔巨噬细胞募集、激活和抗原提呈功能的影响。在赋形剂处理的小鼠中，SRBC注射在腹膜腔内引起典型的炎症反应。在6小时内，中性粒细胞数量增加，并一直保持到40小时。巨噬细胞数量在24小时后增加，并在72小时内保持高水平。在TCDD处理的小鼠中，观察到SRBC的高炎症反应。与赋形剂处理的小鼠相比，SRBC攻击后16、24和40小时的腹膜渗出细胞总数显著增加。腹膜细胞数量的增加反映了中性粒细胞和巨噬细胞的显著增加。于注射SRBC后第0~3d，用双色流式细胞仪检测Mac-1+腹膜细胞活化标志物F4/80和I-A的表达。SRBC刺激后24-72小时，F4/80荧光强度显著降低，而与I-A相关的荧光强度在72小时显著增加。这些变化与巨噬细胞的激活相一致。TCDD没有显著改变Mac-1+细胞上F4180的表达，而TCDD处理的小鼠细胞上I-A表达较早增加。然而，TCDD治疗并没有改变腹膜细胞的抗原提呈功能，这是通过它们在体外诱导SRBC诱导的T细胞增殖的能力来评估的。TCDD暴露对贴壁脾细胞的抗原提呈功能也没有影响。为了验证TCDD处理的小鼠中过量的吞噬细胞更有效地清除抗原，导致较小的(例如，抑制的)抗体反应的假设，我们试图通过增加用于挑战的SRBC抗原的量来克服TCDD抑制。然而，TCDD处理的小鼠的抗SRBC反应的大小并没有随着抗原攻击剂量的增加而显著改变，这表明巨噬细胞对抗原的增强清除不是TCDD抑制抗SRBC反应的机制之一。炎症反应增强的机制(S)及其与TCDD免疫毒性的关系(如果有)仍有待阐明。
TCDD is a widespread environmental contaminant of concern to human health because of its well-recognized immunotoxicity in laboratory animals. Suppression of the murine antibody response to xenogeneic erythrocytes has been shown to be one of the most sensitive assays for TCDD immunotoxicity. However, the cellular mechanisms underlying the suppressed immune function have not been fully elucidated. In the present studies, peritoneal macrophage recruitment, activation, and antigen-presenting function in response to sheep red blood cell (SRBC) injection were compared in C57B1/6 mice treated with a single oral dose of 0 or 5 μg TCDD/kg. In vehicle-treated mice, SRBC injection induced a typical inflammatory response in the peritoneal cavity. Within 6 hr, the number of neutrophils increased and remained elevated until 40 hr. Macrophage numbers increased at 24 hr and remained elevated through 72 hr. In TCDD-treated mice, a hyperinflammatory response to SRBC was observed. The total number of peritoneal exudate cells was significantly greater at 16, 24, and 40 hr after SRBC challenge when compared to that of vehicle-treated mice. The increased number of peritoneal cells reflected significant increases in both neutrophils and macrophages. Mac-1+peritoneal cells were examined by two-color flow cytometric analysis on Days 0-3 after SRBC injection for expression of the activation markers F4/80 and I-A. The intensity of F4/80 fluorescence significantly decreased 24-72 hr following SRBC challenge, while fluorescence associated with I-A significantly increased at 72 hr. These changes are consistent with macrophage activation. TCDD did not significantly alter F4180 expression on Mac-1+cells, whereas I-A expression was increased earlier on cells from TCDD-treated mice. However, TCDD treatment did not alter the antigen presentation function of peritoneal cells, assessed by their ability to induce the proliferation of SRBC-primed T cells in vitro. The antigen-presenting function of adherent spleen cells was also not altered by TCDD exposure. To test the hypothesis that an excess number of phagocytes in TCDD-treated mice were clearing the antigen more efficiently, leading to a smaller (e.g., suppressed) antibody response, we attempted to overcome TCDD suppression by increasing the amount of SRBC antigen used for challenge. However, the magnitude of the anti-SRBC response in TCDD-treated mice was not significantly altered by increasing the antigen challenge dose, suggesting that enhanced clearance of antigen by macrophage is not a mechanism for TCDD-induced suppression of the anti-SRBC response. The mechanism(s) for the enhanced inflammatory response and its relationship, if any, to TCDD immunotoxicity remain to be elucidated.