Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Ohno-Higashi, Osaka-Sayama, Osaka, Japan.
Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Int Immunol. 2019 Sep 18;31(10):669-683. doi: 10.1093/intimm/dxz045.
Previous studies have shown that inhibition of receptor-interacting serine/threonine kinase (RICK) (also known as RIP2) results in amelioration of experimental colitis. This role has largely been attributed to nucleotide-binding oligomerization domain 2 (NOD2) signaling since the latter is considered a major inducer of RICK activation. In this study, we explored the molecular mechanisms accounting for RICK-mediated inhibition of inflammatory bowel disease (IBD). In an initial series of studies focused on trinitrobenzene sulfonic acid (TNBS)-colitis and dextran sodium sulfate (DSS)-colitis we showed that down-regulation of intestinal RICK expression in NOD2-intact mice by intra-rectal administration of a plasmid expressing RICK-specific siRNA was accompanied by down-regulation of pro-inflammatory cytokine responses in the colon and protection of the mice from experimental colitis. Somewhat surprisingly, intra-rectal administration of RICK-siRNA also inhibited TNBS-colitis and DSS-colitis in NOD2-deficient and in NOD1/NOD2-double deficient mice. In complementary studies of humans with IBD we found that expression of RICK, cellular inhibitor of apoptosis protein 2 (cIAP2) and downstream signaling partners were markedly increased in inflamed tissue of IBD compared to controls without marked elevations of NOD1 or NOD2 expression. In addition, the increase in RICK expression correlated with disease activity and pro-inflammatory cytokine responses. These studies thus suggest that NOD1- or NOD2-independenent activation of RICK plays a major role in both murine experimental colitis and human IBD.
先前的研究表明，抑制受体相互作用丝氨酸/苏氨酸激酶（RICK）（也称为 RIP2）可改善实验性结肠炎。由于后者被认为是 RICK 激活的主要诱导剂，因此该作用主要归因于核苷酸结合寡聚结构域 2（NOD2）信号。在这项研究中，我们探讨了导致 RICK 介导的抑制炎症性肠病（IBD）的分子机制。在最初的一系列针对三硝基苯磺酸（TNBS）结肠炎和葡聚糖硫酸钠（DSS）结肠炎的研究中，我们表明，通过直肠内给予表达 RICK 特异性 siRNA 的质粒下调 NOD2 完整小鼠的肠道 RICK 表达，伴随着结肠中促炎细胞因子反应的下调，并保护小鼠免受实验性结肠炎的侵害。令人有些惊讶的是，直肠内给予 RICK-siRNA 也抑制了 NOD2 缺陷型和 NOD1/NOD2 双缺陷型小鼠的 TNBS 结肠炎和 DSS 结肠炎。在对 IBD 患者的互补研究中，我们发现与对照组相比，IBD 患者的 RICK、细胞凋亡抑制剂蛋白 2（cIAP2）和下游信号伙伴的表达在炎症组织中明显增加，而 NOD1 或 NOD2 的表达没有明显升高。此外，RICK 表达的增加与疾病活动度和促炎细胞因子反应相关。这些研究表明，RICK 的 NOD1 或 NOD2 非依赖性激活在小鼠实验性结肠炎和人类 IBD 中均发挥重要作用。
