Kishikawa H, Song R, Lawrence D A
Department of Pharmacology and Neuroscience, Albany Medical College, New York 12208, USA.
Toxicol Appl Pharmacol. 1997 Dec;147(2):180-9. doi: 10.1006/taap.1997.8308.
The heavy metal lead (Pb) has been shown to downregulate various parameters of cell-mediated immune (CMI) responses. This inhibition of CMI responses by Pb is exemplified by a higher mortality rate upon infections with sublethal doses of a variety of pathogens. Unlike Pb, which lowers host resistance, interleukin-12 (IL-12) exerts a substantial stimulatory influence on the host response to intracellular bacteria such as Listeria monocytogenes. To explore the influence of IL-12 in mice rendered susceptible to Listerial infection by oral exposure to Pb, we determined bacterial burdens and production of interferon gamma (IFN-gamma). As expected, Pb-exposed mice had increased morbidity due to higher Listerial titers as compared to control mice. However, administration of exogenous IL-12 reversed the Pb-induced inhibition of host defense and boosted the resistance of the non-Pb-treated mice. The enhanced CMI responses observed in both IL-12-treated groups were accompanied with elevations of IFN-gamma in the sera and spleens. Significant reduction in the number of viable Listeria in Pb-exposed mice upon IL-12 administration suggests that the processes downstream of IL-12 production were intact in the Pb-exposed mice and that the inhibition by Pb was due to the lack of functional IL-12. Alternatively, the exogenous IL-12 may have overcome a downstream effect by enhancing an secondary pathway. Support for the former hypothesis is based on the observation that Pb induced elevated levels of p40 splenic messenger RNA since increased p40 expression would result from lack of IL-12 formation. Contrary to the IFN-gamma levels, significantly higher levels of IL-6 and corticosterone were observed in the sera and spleens of Pb-exposed mice upon infection, suggesting heightened stress in the absence of IL-12. Overall, the results suggest that an environmental pollutant such as Pb can enhance the stress response, which naturally occurs during an infection, and can further compromise health by lowering host resistance by altering cytokine levels.
重金属铅（Pb）已被证明会下调细胞介导免疫（CMI）反应的各种参数。Pb对CMI反应的这种抑制作用表现为，感染亚致死剂量的多种病原体后死亡率更高。与降低宿主抵抗力的Pb不同，白细胞介素-12（IL-12）对宿主对细胞内细菌（如单核细胞增生李斯特菌）的反应具有显著的刺激作用。为了探究IL-12对经口服暴露于Pb而易患李斯特菌感染的小鼠的影响，我们测定了细菌载量和干扰素γ（IFN-γ）的产生。正如预期的那样，与对照小鼠相比，暴露于Pb的小鼠因李斯特菌滴度较高而发病率增加。然而，给予外源性IL-12可逆转Pb诱导的宿主防御抑制，并增强未接受Pb处理小鼠的抵抗力。在两个接受IL-12治疗的组中观察到的增强的CMI反应伴随着血清和脾脏中IFN-γ水平的升高。给予IL-12后，暴露于Pb的小鼠体内存活的李斯特菌数量显著减少，这表明暴露于Pb的小鼠中IL-12产生的下游过程是完整的，且Pb的抑制作用是由于缺乏功能性IL-12。或者，外源性IL-12可能通过增强一条次要途径克服了下游效应。对前一种假设的支持基于以下观察结果：Pb诱导脾脏p40信使核糖核酸水平升高，因为p40表达增加是由于缺乏IL-12形成所致。与IFN-γ水平相反，感染后在暴露于Pb的小鼠的血清和脾脏中观察到IL-6和皮质酮水平显著更高，这表明在缺乏IL-12的情况下应激加剧。总体而言，结果表明，诸如Pb之类的环境污染物可增强感染期间自然发生的应激反应，并可通过改变细胞因子水平降低宿主抵抗力而进一步损害健康。
