Kanai T, Watanabe M, Okazawa A, Nakamaru K, Okamoto M, Naganuma M, Ishii H, Ikeda M, Kurimoto M, Hibi T
Keio Cancer Center, Tokyo, Japan.
Gastroenterology. 2000 Dec;119(6):1514-23. doi: 10.1053/gast.2000.20260.
BACKGROUND & AIMS: Crohn's disease (CD) is characterized by a marked accumulation of activated Th1 type CD4(+) T cells and macrophages in inflamed intestinal mucosa. Interleukin (IL)-18 is a recently described cytokine that mainly exists in activated macrophages and shares biological activities with IL-12 in driving the development of Th1 type CD4(+) T cells by inducing interferon gamma. To clarify the role of IL-18 in intestinal inflammation in CD, we assessed the functional role of IL-18 in regulating intestinal mucosal lymphocytes.
Serum IL-18 concentration was measured by enzyme-linked immunosorbent assay. Expression of IL-18 and IL-18 receptor in human intestinal mucosa was determined using immunohistochemistry and flow cytometry. The functional activity of IL-18 was assessed by the use of recombinant IL-18 to stimulate both the growth of intestinal mucosal lymphocytes and IL-2 receptor induction activity.
The serum IL-18 concentration was significantly higher in patients with CD than normal controls. In the inflamed colonic mucosa of CD, many IL-18(+)CD68(+) macrophages had infiltrated the lamina propria. Intestinal mucosal lymphocytes from CD expressed functional IL-18 receptors. Recombinant IL-18 induced significant proliferative responses in freshly isolated mucosal lymphocytes from CD patients, but not from normal controls. IL-18 up-regulated IL-2 receptor expression in mucosal lymphocytes from patients with CD, but not from normal controls.
These findings suggest that infiltrated macrophages in the inflamed intestinal mucosa in CD produce IL-18, and that macrophage-derived IL-18 may serve as a potent regulatory factor for intestinal mucosal lymphocytes, thereby contributing to chronic intestinal inflammation in CD.
克罗恩病（CD）的特征是在炎症性肠黏膜中活化的Th1型CD4(+) T细胞和巨噬细胞显著积聚。白细胞介素（IL）-18是一种最近发现的细胞因子，主要存在于活化的巨噬细胞中，在通过诱导γ干扰素驱动Th1型CD4(+) T细胞发育方面与IL-12具有共同的生物学活性。为阐明IL-18在CD肠道炎症中的作用，我们评估了IL-18在调节肠黏膜淋巴细胞中的功能作用。
采用酶联免疫吸附测定法检测血清IL-18浓度。使用免疫组织化学和流式细胞术测定人肠黏膜中IL-18和IL-18受体的表达。通过使用重组IL-18刺激肠黏膜淋巴细胞的生长和IL-2受体诱导活性来评估IL-18的功能活性。
CD患者血清IL-18浓度显著高于正常对照组。在CD的炎症性结肠黏膜中，许多IL-18(+)CD68(+)巨噬细胞浸润到固有层。来自CD的肠黏膜淋巴细胞表达功能性IL-18受体。重组IL-18在来自CD患者的新鲜分离的黏膜淋巴细胞中诱导了显著的增殖反应，但在正常对照组中未诱导。IL-18上调了CD患者黏膜淋巴细胞中IL-2受体的表达，但在正常对照组中未上调。
这些发现表明，CD炎症性肠黏膜中浸润的巨噬细胞产生IL-18，并且巨噬细胞衍生的IL-18可能作为肠黏膜淋巴细胞的有效调节因子，从而导致CD中的慢性肠道炎症。
