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: 7845610
• 负责人: Aiping Zhao
• 金额: $ 37.13万
• 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/7845610
• 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; Source; Therapeutic Agents; Up-Regulation; arm; cell type; combat; cytokine; interleukin-17E; macrophage; member; novel; pathogen; public health relevance; 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）：宿主防御的进化以对抗多种病原体为特征，部分是通过向辅助性T (Th) 1或Th2细胞因子谱极化。th17细胞因子家族的鉴定为慢性炎症的适应性免疫反应提供了新的途径。宿主内稳态依赖于个体细胞谱系之间的微妙平衡，这种平衡部分是通过细胞因子的相互调节来控制的。众所周知，病原体诱导的Th1和Th2细胞因子的上调会诱导肠道平滑肌和上皮细胞反应的刻板变化，有时是相反的变化，这对宿主耐药性很重要。Th细胞因子谱之间的失衡、高或低反应性或缺乏协调与肠道功能失调有关，并且是包括炎症性肠病（IBD）在内的许多肠道粘膜炎症的特征。目前，还没有治愈IBD的方法，也没有现有的药物可以缓解所有患者的病情。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。这可能与以Th1/Th17基因型为主的克罗恩病更相关。IL-25 （IL-17E）是一种新发现的细胞因子，是IL-17细胞因子家族的成员。与该家族的其他细胞因子不同，IL-25促进Th2，抑制Th1和Th17，细胞因子反应，从而作为肠道黏膜炎症的关键调节因子。IL-25促进Th2和/或抑制Th1/Th17反应的能力所涉及的细胞类型和机制，特别是在结肠中，尚不清楚。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-17RA和IL-17RB，暗示该细胞因子是粘膜免疫的关键成分。本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th2介导的免疫和肠道功能变化中起关键作用。这个项目有三个具体目标。特异性Aim 1将描述线虫感染诱导结肠上皮细胞IL-25上调的机制和结果。我们假设IL-4/IL-13和IL-25之间存在相互调节，促进th2介导的宿主保护性免疫。我们将1)确定小鼠T. muris感染期间结肠中产生和/或响应IL-25的细胞群以及IL-25/IL- 17RA/IL- 17rb免疫调节的潜在机制；2)通过IL-4/IL-13激活STAT6直接诱导结肠上皮细胞IL-25/IL-17RA/IL-17RB表达；3)研究IL-25通过巨噬细胞促进Th2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Aim 2将确定IL-25在结肠功能免疫调节中的作用。我们假设IL-25对上皮和平滑肌功能有直接和间接的影响，这对有效的Th2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STAT6的依赖性；3)建立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Aim 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因子，IL-25免疫反应的失调在结肠炎症中起重要作用。我们将1)确定IL-25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或恶唑酮诱导结肠炎病程的影响；3)研究IL-25通过TLR信号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确定IL-25是结肠中关键的免疫调节细胞因子。此外，这些研究将确定IL-25的功能影响，以及在Th1- （tnbs诱导）和Th2- （T. muris诱导）优势病理过程中IL-25和IL-25受体表达的调控机制。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，还没有治愈IBD的方法，也没有现有的药物可以缓解所有患者的病情。IL-25是新发现的具有抗炎作用的细胞因子。目前的研究提供了一种系统的方法来确定IL-25作为肠道中关键的免疫调节细胞因子，希望将其发展成为th1介导的病理（如IBD）的治疗剂。