Toll-like receptors and intestinal inflammation

人类的肠道中藏有大量共生微生物。几种临床观察和动物实验 实验表明，肠道细菌在慢性肠道疾病的发病机制中起主要作用。 发炎。肠道侵袭性病原体，如沙门氏菌、志贺氏菌、耶尔森氏菌和李斯特菌可入侵 上皮细胞，并引发炎症反应。鞭毛蛋白是细菌鞭毛的主要成分， 从各种细菌释放，包括共生菌或肠道侵袭性微生物，并刺激Toll样蛋白 受体(TLR)5，在肠上皮细胞中高表达。我们最近的结果显示，在非 鞭毛蛋白刺激特异性诱导转化的人结肠细胞和正常人结肠细胞 炎性基因表达是IBD病理生理学的一个显著特征。尽管如此， 结果，细菌鞭毛蛋白在结肠细胞和结肠细胞中传递促炎反应的机制 自然的结肠粘膜仍然知之甚少。这项提议的中心假设是 由于损伤或腐蚀性病原体的损害，上皮屏障功能受损，使细菌鞭毛能够 穿透渗漏的上皮细胞，激活基底外侧TLR5，导致结肠炎。我们的目标是 鞭毛蛋白在人体内发挥促炎作用的信号通路(S) 并检测细菌鞭毛蛋白在结肠发生发展中的作用。 小鼠结肠炎模型中的炎症反应。目的1研究导致IL-8和IL-8的信号转导途径(S) 鞭毛蛋白对未转化人结肠NCM460细胞MIP-3a基因表达的影响在这一目标中 我们将确定参与鞭毛蛋白暴露反应中MEK磷酸化的特定激酶(S)和 检测它们对TLR5依赖的IL-8和MIP-3a基因表达的影响。实验以确定 磷酸酶MKP-1放大鞭毛诱导的促炎反应的信号机制(S) 并提出了相应的对策。目的2将研究PI-3K信号在TLR5相关的IL-8和 MIP-3a基因在人结肠细胞中的表达。目标3将研究鞭毛蛋白在糖尿病进展中的作用。 结肠炎使用小鼠结肠炎模型，并确定人类的基侧或腔面 小鼠结肠粘膜对鞭毛蛋白有反应。我们提议的研究将提供有意义的 与结肠炎的发病机制相关的信息，包括IBD。

The human gut harbors a large collection of commensal microbes. Several clinical observations and animal experiments suggested that intestinal bacteria play a major role in the pathogenesis of chronic bowel inflammation. Enteroinvasive pathogens such as Salmonella, Shigella, Yersinia, and Listeria can invade the epithelium and provoke inflammatory responses. Flagellin, a major component of bacterial flagellar, is released from various bacteria, including commensal or enteroinvasive microbes, and stimulates Toll-like receptor (TLR) 5 that is highly expressed in intestinal epithelium. Our recent results showed in non- transformed human colonocytes, as well as normal human colon that flagellin stimulation specifically induces proinflammatory gene expression, a prominent characteristic of the pathophysiology of IBD. In spite of these findings, the mechanisms by which bacterial flagellin signals proinflammatory responses in colonocytes and native colonic mucosa remain poorly understood. The central hypothesis of this proposal is that compromised epithelial barrier function, either by injury or by erosive pathogens, enables bacterial flagellin to penetrate the leaky epithelium and activate basolateral TLR5 leading to colonic inflammation. Our goals are to elucidate the signaling pathways by which flagellin exert its proinflammatory action(s) in human colonocytes and examine the participation of bacterial flagellin in the development and progress of colonic inflammation in mouse colitis models. Aim 1 will study the signal transduction pathway(s) leading to IL-8 and MIP-3a gene expression in response to flagellin in non-transformed human colonic NCM460 cells. In this aim we will identify the specific kinase(s) involved in MEK phosphorylation in response to flagellin exposure and examine their involvement in TLR5-dependent IL-8 and MIP-3a gene expression. Experiments to determine the signaling mechanism(s) by which the phosphatase MKP-1 amplifies flagellin-induced proinflammatory responses are also proposed. Aim 2 will examine the role of PI-3K signaling in TLR5-associated IL-8 and MIP-3a gene expression in human colonocytes. Aim 3 will examine the role of flagellin in the progress of colitis using mouse models of colitis and determine whether the basolateral or luminal aspect of the human and mouse colonic mucosa is responsive to flagellin. Our proposed studies will provide significant information relevant to the pathogenesis of colonic inflammation, including IBD.