Shanley T P, Vasi N, Denenberg A
Division of Critical Care Medicine, Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA.
Cytokine. 2000 Jul;12(7):1054-64. doi: 10.1006/cyto.1999.0655.
We have been interested in understanding the mechanisms regulating the inflammatory process underlying acute lung injury. The current studies have employed a model of acute lung inflammation in mice triggered by bacterial lipopolysaccharide. The development of this injury was associated with increased expression of the chemokines, MIP-1alpha and MIP-2, that coordinate recruitment of neutrophils to the lung. IL-10 is a potent, endogenous anti-inflammatory molecule that has been shown to decrease lung inflammation partly on the basis of TNF-alpha and IL-1beta inhibition. In these studies we tested the hypothesis that endogenous IL-10 modulates chemokine expression using the IL-10 knock-out mouse, and then explored the molecular mechanisms by which IL-10 might do so. The results demonstrate that significant elevations in both chemokines were observed in the absence of IL-10 and that these findings were associated with significant increases in lung neutrophil accumulation. In vitro studies defined two, gene-specific, mechanisms by which IL-10 regulated chemokine expression: mRNA destabilization and NF-kappaB inhibition. These results suggested that IL-10 is an important, endogenous regulator of chemokine expression in acute lung inflammation.
我们一直致力于了解调节急性肺损伤潜在炎症过程的机制。目前的研究采用了由细菌脂多糖引发的小鼠急性肺炎症模型。这种损伤的发展与趋化因子MIP-1α和MIP-2表达的增加有关，这两种趋化因子协同作用将中性粒细胞募集到肺部。IL-10是一种强效的内源性抗炎分子，已证明它部分基于对TNF-α和IL-1β的抑制作用来减轻肺部炎症。在这些研究中，我们使用IL-10基因敲除小鼠检验了内源性IL-10调节趋化因子表达的假设，然后探究了IL-10可能发挥此作用的分子机制。结果表明，在缺乏IL-10的情况下，两种趋化因子均显著升高，并且这些发现与肺部中性粒细胞积聚的显著增加相关。体外研究确定了IL-10调节趋化因子表达的两种基因特异性机制：mRNA去稳定化和NF-κB抑制。这些结果表明，IL-10是急性肺炎症中趋化因子表达的重要内源性调节因子。
