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: 8055061
• 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/8055061
• 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; Health; 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The pathogenesis of inflammatory bowel disease is not fully understood, but is associated with over-produced pro-inflammatory cytokines. Currently, there is no cure for IBD and no existing medication induces remission in all patients. IL-25 is a newly-identified cytokine and has anti-inflammatory effect. Current studies provide a systematic approach to establish IL-25 as a key immune regulatory cytokine in the gut in hoping to develop it into a therapeutic agent for Th1-medated pathologies, such as IBD.

描述（由申请人提供）：宿主抵抗多种病原体的防御进化的特征部分在于向T辅助细胞（Th）1或Th 2细胞因子谱的极化。Th 17细胞因子家族的鉴定为适应性免疫反应提供了一个新的分支，这对慢性炎症很重要。宿主体内平衡依赖于个体Th细胞谱系之间的微妙平衡，所述Th细胞谱系部分地通过细胞因子的相互调节来控制。已知病原体诱导的Th 1细胞因子相对于Th 2细胞因子的上调诱导肠平滑肌和上皮细胞应答中的刻板的和有时相反的变化，这对于宿主抗性是重要的。Th细胞因子谱之间的不平衡、高或低反应性或缺乏协调与肠道功能失调相关，并且是包括炎性肠病（IBD）在内的许多肠道粘膜炎性病症的特征。目前，IBD没有治愈方法，也没有现有的药物能在所有患者中诱导缓解。控制IBD的一种方法是通过增加Th 2细胞因子来纠正细胞因子失衡。这可能与克罗恩病更相关，克罗恩病由Th 1/Th 17谱主导。IL-25（IL-17 E）是一种新发现的细胞因子，属于IL-17细胞因子家族。与该家族中的其他细胞因子不同，IL-25促进Th 2，同时抑制Th 1和Th 17细胞因子应答，从而充当肠粘膜中炎症的关键调节剂。涉及IL-25促进Th 2和/或抑制Th 1/Th 17应答的能力的细胞类型和机制，特别是在结肠中，是未知的。关于炎症期间IL- 25的调节或其对肠道功能相关变化的贡献的信息很少。我们的初步数据表明，上皮细胞是IL-25的主要来源，也表达IL-25受体IL-17 RA和IL-17 RB，暗示这种细胞因子是粘膜免疫的关键组分。该项目的中心假设是上皮来源的IL-25在调节粘膜免疫和屏障功能以及促进Th 2介导的免疫和肠道功能变化中起关键作用。该项目有三个具体目标。具体目标1将描述线虫感染诱导的结肠上皮细胞中IL-25上调的机制和结果。我们推测IL-4/IL-13和IL-25之间存在相互调节，促进Th 2介导的宿主保护性免疫。我们将1）鉴定结肠中产生和/或应答IL-25的细胞群以及T期间小鼠中IL-25/IL-17 RA/IL-17 RB的免疫调节的潜在机制。小鼠感染; 2）研究IL-4/IL-13激活STAT 6对结肠上皮细胞IL-25/IL-17 RA/IL-17 RB表达的直接诱导作用; 3）研究IL-25通过巨噬细胞促进Th 2免疫应答; 4）确定线虫或其产物对上皮细胞IL-25的直接诱导作用。特异性目的2将确定IL-25在结肠功能的免疫调节中的作用。我们假设IL-25对上皮和平滑肌功能有直接和间接的影响，而上皮和平滑肌功能对有效的Th 2保护性免疫至关重要。我们将1）确定IL-25在结肠功能的生理和病理生理控制中的作用; 2）研究外源性IL- 25诱导的结肠功能改变对IL-4、IL-13和STAT 6的依赖性; 3）确定IL-25对结肠上皮通透性的直接影响; 4）确定IL-25对结肠平滑肌收缩的直接影响。特异性目的3将确定IL-25在结肠炎症中的作用。我们假设IL-25是肠道免疫稳态的关键调节剂，IL-25免疫应答的失调在结肠炎症中起重要作用。我们将1）确定IL-25的缺陷是否影响小鼠对结肠炎症的易感性; 2）评估外源性IL-25对TNBS或恶唑酮诱导的结肠炎过程的影响; 3）研究IL-25通过TLR信号传导调节先天免疫应答的作用。这些研究提供了一种系统的方法来建立IL-25作为结肠中的关键免疫调节细胞因子。此外，这些研究将确定IL- 25的功能影响以及在Th 1-（TNBS诱导的）和Th 2-（T.鼠诱导的）显性病理。 公共卫生相关性：炎症性肠病的发病机制尚不完全清楚，但与过度产生的促炎细胞因子有关。目前，IBD没有治愈方法，也没有现有的药物能在所有患者中诱导缓解。IL-25是一种新发现的细胞因子，具有抗炎作用。目前的研究提供了一种系统的方法来建立IL-25作为肠道中的关键免疫调节细胞因子，希望将其开发成Th 1介导的病理学（如IBD）的治疗剂。