Novel Cytokine Regulation of Gut Function and Inflammation

肠道功能和炎症的新型细胞因子调节

• 批准号: 8247779
• 负责人: Aiping Zhao
• 金额: $ 25.73万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8247779
• 关键词: Abnormal coordination; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Cell Lineage; Cells; Characteristics; Chronic; Colitis; Colon; Crohn' s disease; Data; Defect; Dependence; Disease remission; Epithelial; Epithelial Cells; Equilibrium; Evolution; Family; Homeostasis; Host Defense; Host resistance; Immune; Immune response; Immunity; Individual; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-13; Interleukin-17; Interleukin-4; Intestines; Mediating; Mucosal Immunity; Mucous Membrane; Mus; Muscle Contraction; Muscle function; Nematoda; Nematode infections; Outcome; Oxazolone; Pathogenesis; Pathology; Patients; Permeability; Pharmaceutical Preparations; Physiological; Play; Population; Predisposition; Regulation; Role; STAT6 gene; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Source; Therapeutic Agents; Up-Regulation; arm; cell type; combat; cytokine; interleukin-17E; macrophage; member; novel; pathogen; receptor; receptor expression; response

PROJECT SUMMARY Evolution of host defense to combat a multitude of pathogens is characterized, in part, by polarization towards either the T helper (Th) 1 or Th2 cytokine profile. The identification of theTh17 cytokine family provides a new arm of the adaptive immune response that is important for chronic inflammation. Host homeostasis relies on the delicate balance among the individual Th cell lineages that are controlled, in part, through reciprocal regulation of the cytokines. It is known that pathogen-induced up-regulation of Th1 vs Th2 cytokines induces stereotypic and sometimes opposing changes in gut smooth muscle and epithelial cell responses that are important for host resistance. An imbalance, hyper- or hypo-responsiveness, or lack of coordination among the Th cytokine profiles, is associated with dysregulation of gut function and is a characteristic of a number of mucosal inflammatory conditions of the gut including inflammatory bowel disease (IBD). Currently, there is no cure for IBD and no existing medication induces remission in all patients. One approach to control IBD is to rectify the cytokine imbalance by increasing Th2 cytokines. This may be more relevant to Crohn's disease, which is dominated by Th1/Th17 profile. IL-25 (IL-17E) is a newly-identified cytokine and a member of the IL-17 cytokine family. Unlike other cytokines in this family, IL-25 promotes Th2 while suppress Th1 and Th17, cytokine responses, thereby serving as a key regulator of inflammation in the gut mucosa. The cell types and mechanisms involved in IL-25's ability to promote Th2 and/or suppress Th1/Th17 response, particularly in the colon, are unknown. There is little information on the regulation of IL- 25 during inflammation or its contribution to the associated changes in gut function. Our preliminary data show that epithelial cells are a major source of IL-25 and also express IL-25 receptors IL-17RA and IL-17RB implicating this cytokine as a key component in mucosal immunity. The central hypothesis of this project is that epithelial derived IL-25 plays a key role in modulating mucosal immunity and barrier function as well as promoting the Th2-mediated changes in immune and gut function. There are 3 specific aims in this project. Specific Aim 1 will characterize the mechanism and outcome of nematode infection-induced up-regulation of IL-25 in colonic epithelial cells. We hypothesize that there is a reciprocal regulation between IL-4/IL-13 and IL-25 that promotes Th2-mediated host protective immunity. We will 1) identify the cell populations in the colon that produce and/or respond to IL-25 and the underlying mechanism of immune regulation of IL-25/IL- 17RA/IL-17RB in mice during T. muris infection; 2) investigate the direct induction of IL-25/IL-17RA/IL-17RB expression in colonic epithelial cell by IL-4/IL-13 activation of STAT6; 3) investigate IL-25 promoting Th2 immune response via macrophages; and 4) Determine the direct induction of IL-25 by nematode or the product in epithelial cells. Specific Aim 2 will determine the role of IL-25 in the immune regulation of colonic function. We hypothesize that IL-25 has both direct and indirect effects on epithelial and smooth muscle function that are critical to an effective Th2 protective immunity. We will 1) Determine the role of IL-25 in the physiologic and pathophysiologic control of colonic function; 2) Investigate the dependence of exogenous IL- 25-induced alterations in colonic function on IL-4, IL-13, and STAT6; 3) Establish the direct effects of IL-25 on colonic epithelial permeability; and 4) Determine the direct effects of IL-25 on colonic smooth muscle contraction. Specific Aim 3 will determine the role of IL-25 in colonic inflammation. We hypothesize that IL-25 is a critical regulator of intestinal immune homeostasis and dysregulation of IL-25 immune responses plays an important role in colonic inflammation. We will 1) Determine whether a defect in IL-25 affects the susceptibility of mice to colonic inflammation; 2) Assess the effects of exogenous IL-25 on the course of TNBS-or oxazolone-induced colitis; and 3) Investigate the role of IL-25 in modulating the innate immune response through TLR signaling. These studies provide a systematic approach to establish IL-25 as a key immuno- regulatory cytokine in the colon. In addition, these studies will establish the functional impact of IL- 25 as well as the mechanisms involved in regulation of IL-25 and IL-25 receptor expression during Th1- (TNBS-induced) and Th2- (T. muris-induced) dominant pathologies.

项目总结 抗击多种病原体的寄主防御进化的部分特征是极化。 T辅助细胞(Th)1或Th2细胞因子谱。Th17细胞因子家族的鉴定 提供了一种新的适应性免疫反应，这对慢性炎症很重要。寄主 动态平衡依赖于个体Th细胞谱系之间的微妙平衡，这些细胞系在一定程度上受到控制， 通过细胞因子的相互调节。已知病原体诱导Th1对Th2的上调 细胞因子诱导肠道平滑肌和上皮细胞的刻板变化，有时甚至相反的变化 对寄主抗性很重要的反应。反应不平衡、反应过度或反应迟钝 Th细胞因子之间的协调，与肠道功能失调有关，是一种 包括炎症性肠炎在内的多种肠黏膜炎症状况的特点 疾病(IBD)。目前，没有治愈IBD的方法，也没有现有的药物可以缓解所有患者。 控制IBD的一种方法是通过增加Th2细胞因子来纠正细胞因子失衡。这可能是 与克罗恩病更相关，该病以Th1/Th17谱为主。白介素25(IL-17E)是一种新发现的 细胞因子和IL-17细胞因子家族的成员。与这个家族中的其他细胞因子不同，IL-25促进Th2 同时抑制Th1和Th17，细胞因子反应，从而发挥炎症的关键调节作用 肠黏膜。IL-25参与S促进Th2和/或抑制Th2的细胞类型和机制 Th1/Th17反应，特别是在结肠中，是未知的。关于IL-2的调控信息很少。 25在炎症期间或其对相关的肠道功能改变的贡献。我们的初步数据 显示上皮细胞是IL-25的主要来源，也表达IL-25受体IL-17RA和IL-17RB 暗示这种细胞因子是粘膜免疫中的关键成分。这个项目的中心假设是 上皮源性IL-25在调节黏膜免疫和屏障功能中起关键作用 促进Th2介导的免疫和肠道功能改变。这个项目有三个具体目标。 具体目标1将描述线虫感染诱导的上调的机制和结果 IL-25在结肠上皮细胞中表达。我们假设IL-4/IL-13和IL-13之间存在相互调节。 IL-25促进Th2介导的宿主保护性免疫。我们将1)确定细胞群在 产生和/或对IL-25产生和/或应答的结肠以及IL-25/IL-25免疫调节的潜在机制 小鼠感染毛滴虫时17RA/IL-17RB的表达；2)研究IL-25/IL-17RA/IL-17RB的直接诱导作用 IL-4/IL-13激活STAT6在结肠上皮细胞中的表达；3)IL-25促进Th2的表达 通过巨噬细胞的免疫反应；以及4)确定线虫或 上皮细胞中的产物。特异性靶点2将确定IL-25在结肠免疫调节中的作用 功能。我们假设IL-25对上皮和平滑肌有直接和间接的作用 对有效的Th2保护性免疫至关重要的功能。我们将1)确定IL-25在 结肠功能的生理和病理生理调控；2)研究外源性IL-2的依赖性 25诱导的结肠功能改变对IL-4、IL-13和STAT6的影响；3)建立IL-25对 4)确定IL-25对结肠平滑肌的直接作用。 收缩。具体目标3将确定IL-25在结肠炎中的作用。我们假设IL-25 是肠道免疫动态平衡和IL-25免疫反应失调的关键调节因子 在结肠炎中起重要作用。我们将1)确定IL-25的缺陷是否会影响 小鼠对结肠炎的易感性；2)评估外源性IL-25对小鼠结肠炎症过程的影响 3)研究IL-25在调节天然免疫中的作用。 通过TLR信令进行响应。这些研究提供了一种系统的方法来将IL-25确立为关键 结肠中的免疫调节细胞因子。此外，这些研究还将确定IL-1的功能影响。 25以及IL-25和IL-25受体在Th1-T细胞中表达的调节机制。 (TNBS诱导的)和Th2(T.Muris诱导的)显性病理。