Moos A B, Baecher-Steppan L, Kerkvliet N I
College of Veterinary Medicine, Oregon State University, Corvallis 97331.
Toxicol Appl Pharmacol. 1994 Aug;127(2):331-5. doi: 10.1006/taap.1994.1169.
Recent studies have demonstrated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure of C57Bl/6 mice results in an enhanced inflammatory response to intraperitoneal injection of sheep red blood cells (SRBC). This response is characterized by an increase in total peritoneal cells (PEC) as well as an increase in relative and absolute numbers of neutrophils (PMN) harvested 16 to 40 hr following injection of SRBC. The mechanisms whereby TCDD increases cellular influx are unknown. In the present studies, the role of the proinflammatory cytokines interleukin 1 (IL-1) and tumor necrosis factor (TNF) in TCDD-induced hyperinflammation was examined. Intraperitoneal administration of recombinant IL-1 beta (0.4 U) or TNF alpha (10 ng) resulted in an enhanced peritoneal inflammatory response compared to phosphate-buffered saline-injected control animals measured 20 hr following injection of SRBC. The effect of exogenous cytokines mimicked the effects of exposure to 5 micrograms/kg TCDD. When endogenous IL-1 activity was blocked using an IL-1 receptor antagonist (IL-1ra, 1 mg every 3 hr), the PMN influx was significantly decreased in control animals but not in animals exposed to 20 micrograms/kg TCDD. When endogenous TNF activity was blocked using a TNF-soluble receptor (rhuTNFR:Fc, 100 micrograms), the numbers of total PEC and macrophages (MAC) harvested from control mice were reduced, while in mice exposed to 20 micrograms/kg TCDD, inhibition of TNF activity dramatically reduced the numbers of PEC, MAC, and PMN. Following rhTNFR:Fc treatment, there was no difference between TCDD-treated and control mice in inflammatory cell influx. These results demonstrate that TNF plays a major role in mediating TCDD-induced hyperinflammation. In support of this conclusion, a dose-dependent increase in plasma TNF alpha was measured by ELISA in TCDD-treated mice following SRBC injection.
近期研究表明，C57Bl/6小鼠暴露于2,3,7,8-四氯二苯并对二恶英（TCDD）后，对腹腔注射绵羊红细胞（SRBC）的炎症反应增强。这种反应的特征是腹腔细胞总数（PEC）增加，以及在注射SRBC后16至40小时收获的中性粒细胞（PMN）相对数量和绝对数量增加。TCDD增加细胞流入的机制尚不清楚。在本研究中，研究了促炎细胞因子白细胞介素1（IL-1）和肿瘤坏死因子（TNF）在TCDD诱导的过度炎症中的作用。与注射磷酸盐缓冲盐水的对照动物相比，腹腔注射重组IL-1β（0.4 U）或TNFα（10 ng）导致在注射SRBC后20小时测量的腹腔炎症反应增强。外源性细胞因子的作用模拟了暴露于5微克/千克TCDD的效果。当使用IL-1受体拮抗剂（IL-1ra，每3小时1毫克）阻断内源性IL-1活性时，对照动物的PMN流入显著减少，但暴露于20微克/千克TCDD的动物中未减少。当使用TNF可溶性受体（rhuTNFR:Fc，100微克）阻断内源性TNF活性时，从对照小鼠收获的总PEC和巨噬细胞（MAC）数量减少，而在暴露于20微克/千克TCDD的小鼠中，TNF活性的抑制显著减少了PEC、MAC和PMN的数量。rhTNFR:Fc治疗后，TCDD处理的小鼠和对照小鼠在炎症细胞流入方面没有差异。这些结果表明，TNF在介导TCDD诱导的过度炎症中起主要作用。支持这一结论的是，在SRBC注射后，通过ELISA在TCDD处理的小鼠中测量到血浆TNFα呈剂量依赖性增加。
