Division of Experimental Pathology, Institute of Pathology, University of Bern, Murtenstrasse 31, 3010 Bern, Switzerland.
FASEB J. 2010 May;24(5):1340-6. doi: 10.1096/fj.09-140913. Epub 2010 Jan 7.
Stringent control of immune responses in the intestinal mucosa is critical for the maintenance of immune homeostasis and prevention of tissue damage, such as observed during inflammatory bowel disease. Intestinal epithelial cells, primarily thought to form a simple physical barrier, critically regulate intestinal immune cell functions by producing immunoregulatory glucocorticoids on T-cell activation. In this study we investigated whether stimulation of cells of the innate immune system results in the induction of intestinal glucocorticoids synthesis and what role TNF-alpha plays in this process. Stimulation of the innate immune system with lipopolysaccharide (LPS) led to an up-regulation of colonic steroidogenic enzymes and the induction of intestinal glucocorticoid synthesis. The observed induction was dependent on macrophage effector functions, as depletion of macrophages using clodronate-containing liposomes, but not absence of T and B cells, inhibited intestinal glucocorticoid synthesis. LPS-induced glucocorticoid synthesis was critically dependent on TNF-alpha as it was significantly decreased in TNF-alpha-deficient animals. Both TNF receptor-1 and -2 were found to be equally involved in LPS- and T-cell-induced intestinal GC synthesis. These results describe a novel and critical role of TNF-alpha in immune cell-induced intestinal glucocorticoid synthesis.
严格控制肠道黏膜中的免疫反应对于维持免疫稳态和防止组织损伤至关重要，如在炎症性肠病中观察到的那样。肠道上皮细胞主要被认为形成简单的物理屏障，通过在 T 细胞活化时产生免疫调节糖皮质激素，来严格调节肠道免疫细胞的功能。在这项研究中，我们研究了先天免疫系统的刺激是否会导致肠道糖皮质激素合成的诱导，以及 TNF-α在这一过程中扮演什么角色。用脂多糖 (LPS) 刺激先天免疫系统会导致结肠甾体生成酶的上调和肠道糖皮质激素合成的诱导。观察到的诱导依赖于巨噬细胞的效应功能，因为用含有氯膦酸盐的脂质体耗尽巨噬细胞，但不缺乏 T 和 B 细胞，会抑制肠道糖皮质激素的合成。LPS 诱导的糖皮质激素合成严重依赖于 TNF-α，因为在 TNF-α 缺陷动物中，它显著降低。发现 TNF 受体-1 和 -2 都平等地参与 LPS 和 T 细胞诱导的肠道 GC 合成。这些结果描述了 TNF-α在免疫细胞诱导的肠道糖皮质激素合成中的一个新的和关键作用。
