Interleukin 24 in Epidermal Function

描述(申请人提供)：这个R21研究计划的总体目标是揭示IL-24的生理功能，这是我们最近发现的一种新的细胞因子。IL-24属于IL-10细胞因子家族。我们已经鉴定了两个异二聚体的EL-24受体(IL-22R1/IL-20R2和IL-20R1和IL-20R2)，当它们与配体结合时会导致STATS的激活。IL-24受体表达的组织分布分析表明，表皮是IL-24的主要靶向组织之一，而IL-10主要作用于造血祖细胞。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的激活。结果显示，STAT3基因敲除小鼠在伤口愈合过程中表现出缺陷。此外，在皮肤创面愈合过程中，IL-24的表达显著增加，聚集在创面真皮下的浸润性单个核细胞是产生IL-24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讨IL-24信号的生理功能。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，由浸润性单核细胞产生的IL-24可能类似于造血细胞上的IL-10，抑制表皮合成促炎细胞因子，如IL-1和TNF-α。在这一点上，IL-24可能作为一种抗炎细胞因子，在伤口愈合过程中发出减弱或最终终止皮肤炎症反应的信号。其次，在组织修复过程中，IL-24可能是角质形成细胞增殖、迁移和分化的信号。我们的发现支持这一假设，即IL-24可以以IL-24受体依赖的方式替代IL-3作为小鼠IL-3依赖的前B细胞的生存和生长因子。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。我们提出以下特定目的来验证这些假说：特定目的1：通过检测IL-24是否能抑制促炎细胞因子的产生，促进细胞的增殖、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：利用小鼠皮肤切除创面模型和IL-24拮抗剂，探讨IL-24在创面愈合中的作用。

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.