Uhlig Holm H, McKenzie Brent S, Hue Sophie, Thompson Claire, Joyce-Shaikh Barbara, Stepankova Renata, Robinson Nicolas, Buonocore Sofia, Tlaskalova-Hogenova Helena, Cua Daniel J, Powrie Fiona
Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OX1 3RE Oxford, UK.
Immunity. 2006 Aug;25(2):309-18. doi: 10.1016/j.immuni.2006.05.017.
The CD40-CD154 pathway is important in the pathogenesis of inflammatory bowel disease. Here we show that injection of an agonistic CD40 mAb to T and B cell-deficient mice was sufficient to induce a pathogenic systemic and intestinal innate inflammatory response that was functionally dependent on tumor necrosis factor-alpha and interferon-gamma as well as interleukin-12 p40 and interleukin-23 p40 secretion. CD40-induced colitis, but not wasting disease or serum proinflammatory cytokine production, depended on interleukin-23 p19 secretion, whereas interleukin-12 p35 secretion controlled wasting disease and serum cytokine production but not mucosal immunopathology. Intestinal inflammation was associated with IL-23 (p19) mRNA-producing intestinal dendritic cells and IL-17A mRNA within the intestine. Our experiments identified IL-23 as an effector cytokine within the innate intestinal immune system. The differential role of IL-23 in local but not systemic inflammation suggests that it may make a more specific target for the treatment of IBD.
CD40-CD154信号通路在炎症性肠病的发病机制中起重要作用。在此我们表明，向T细胞和B细胞缺陷小鼠注射激动性CD40单克隆抗体足以诱导致病性全身和肠道先天性炎症反应，该反应在功能上依赖于肿瘤坏死因子-α、干扰素-γ以及白细胞介素-12 p40和白细胞介素-23 p40的分泌。CD40诱导的结肠炎，但不是消瘦病或血清促炎细胞因子的产生，依赖于白细胞介素-23 p19的分泌，而白细胞介素-12 p35的分泌控制消瘦病和血清细胞因子的产生，但不控制黏膜免疫病理学。肠道炎症与产生IL-23（p19）mRNA的肠道树突状细胞以及肠道内的IL-17A mRNA相关。我们的实验确定IL-23是肠道先天性免疫系统中的一种效应细胞因子。IL-23在局部而非全身炎症中的不同作用表明，它可能成为治疗炎症性肠病更具特异性的靶点。
