Interleukin 24 in Epidermal Function

白细胞介素 24 对表皮功能的影响

• 批准号: 7229781
• 负责人: PENG LIANG
• 金额: $ 22.92万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-09 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7229781
• 关键词: Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Area; B-Lymphocytes; Binding; Biological Models; Biological Process; Cell Proliferation; Cells; Chronic; Complex; Condition; Cutaneous; Cytokine Activation; Cytokine Network Pathway; Cytokine Signaling; Defect; Dermal; Drug or chemical Tissue Distribution; Epidermis; Excision; Exhibits; Family; Growth Factor; Hematopoietic; Human; Inflammatory Response; Injury; Interleukin-1; Interleukin-10; Interleukin-24; Interleukin-3; Knockout Mice; Ligands; Modeling; Mononuclear; Mus; Numbers; Physiological; Play; Process; Production; Recruitment Activity; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Site; Skin; Source; Testing; Tissues; Wound Healing; attenuation; cytokine; keratinocyte; macrophage; member; migration; monocyte; paracrine; programs; receptor; receptor expression; response; wound

DESCRIPTION (provided by applicant): The overall objective of this R21 research plan is to uncover the physiological functions of IL-24, a new cytokine that we recently discovered. IL-24 belongs to the IL-10 family of cytokines. We have identified two heterodimeric EL-24 receptors (IL-22R1/IL-20R2 and IL-20R1 and IL-20R2) which when bound to the ligand leads to STATs activation. Tissue distribution analysis of IL-24 receptor expression indicates that epidermis is one of the major IL-24 target tissues, in contrast to IL-10, which acts mainly on cells from hemopoeitic lineage. We showed that keratinocyres not only expresses IL-24 receptors but also can be activated by IL-24, which leads to mainly StatS activation. Consistently, stat 3 knockout mice were shown to exhibit defects in wound healing. Furthermore, IL-24 expression was found greatly increased during cutaneous wound healing process, and infiltrating mononuclear cells congregating right beneath the wounded epidermis were shown to be the source of IL-24 production. Logically, here we have selected the wound healing process as a model system to explore the physiological functions of IL-24 signaling. We hypothesize that IL-24 may be an important regulator for at least three keratinocyte functions. First, IL-24 produced by infiltrating monocytes may function, in an analogous manner to IL-10 on hematopoietic cells, to inhibit the synthesis of proinflammatory cytokines such as IL-1 and TNF-a by epidermis. In this regard, IL-24 may function as an anti-inflammatory cytokine that signals the attenuation or ultimate termination of inflammatory responses in the skin during the wound healing process. Secondly, IL-24 may function as a signal for keratinocyte proliferation, migration and differentiation during tissue repair. This hypothesis is supported by our finding that IL-24 could substitute IL-3 as a survival and growth factor for murine IL-3 dependent pro-B cells in IL-24 receptor-dependent manner. Thirdly, IL-24 may be part of a more complex cytokine network involved in the wound healing process. We propose the following specific aims to test these hypothesis: Specific Aim 1: To determine the biological functions of IL-24 on keratinocytes by testing if IL-24 can inhibit the production of proinflammatory cytokines, and promote cell proliferation, migration and differentiation. Specific Aim 2: To determine the role of IL-24 in wound healing using mouse skin excision wound model and IL-24 antagonists.

描述（由申请人提供）：该R21研究计划的总体目标是揭示IL-24的生理功能，IL-24是我们最近发现的一种新细胞因子。IL-24属于细胞因子的IL-10家族。我们已经鉴定了两种异源二聚体EL-24受体（IL-22 R1/IL-20 R2和IL-20 R1和IL-20 R2），其在与配体结合时导致STAT活化。IL-24受体表达的组织分布分析表明，表皮是IL-24的主要靶组织之一，而IL-10主要作用于造血谱系的细胞。我们发现角质形成细胞不仅表达IL-24受体，而且可以被IL-24激活，这主要导致StatS激活。一致地，stat 3敲除小鼠显示出伤口愈合缺陷。此外，发现IL-24表达在皮肤创伤愈合过程中大大增加，并且显示聚集在创伤表皮正下方的浸润单核细胞是IL-24产生的来源。从逻辑上讲，我们选择伤口愈合过程作为模型系统来探索IL-24信号转导的生理功能。我们推测IL-24可能是至少三种角质形成细胞功能的重要调节因子。首先，由浸润的单核细胞产生的IL-24可以以与造血细胞上的IL-10类似的方式起作用，以抑制表皮合成促炎细胞因子如IL-1和TNF-α。在这方面，IL-24可以作为抗炎细胞因子起作用，其在伤口愈合过程中发出减弱或最终终止皮肤中炎症反应的信号。其次，IL-24可能在组织修复过程中作为角质形成细胞增殖、迁移和分化的信号。我们发现IL-24可以以IL-24受体依赖的方式取代IL-3作为小鼠IL-3依赖性pro-B细胞的存活和生长因子，这一假设得到了支持。第三，IL-24可能是参与伤口愈合过程的更复杂的细胞因子网络的一部分。我们提出了以下具体目标来验证这些假设：具体目标1：通过检测IL-24是否可以抑制促炎细胞因子的产生，以及促进细胞增殖、迁移和分化，来确定IL-24对角质形成细胞的生物学功能。具体目的2：使用小鼠皮肤切除伤口模型和IL-24拮抗剂确定IL-24在伤口愈合中的作用。