Interleukin 24 in Epidermal Function

描述（由申请人提供）：本次R21研究计划的总体目标是揭示我们最近发现的一种新的细胞因子IL-24的生理功能。IL-24属于IL-10细胞因子家族。我们已经鉴定出两个异二聚体EL-24受体（IL-22R1/IL-20R2和IL-20R1和IL-20R2），当它们与配体结合时导致STATs激活。IL-24受体表达的组织分布分析表明，表皮是IL-24的主要靶组织之一，而IL-10主要作用于造血细胞。我们发现角化细胞不仅表达IL-24受体，而且可以被IL-24激活，这主要导致StatS的激活。同样，stat 3基因敲除小鼠在伤口愈合方面表现出缺陷。此外，IL-24的表达在皮肤创面愈合过程中显著增加，并表明聚集在伤口表皮下的浸润性单核细胞是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索IL-24信号的生理功能。我们假设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，浸润单核细胞产生的IL-24可能以类似于造血细胞上的IL-10的方式起作用，抑制表皮合成促炎细胞因子，如IL-1和TNF-a。在这方面，IL-24可能作为一种抗炎细胞因子，在伤口愈合过程中表明皮肤炎症反应的衰减或最终终止。其次，IL-24可能在组织修复过程中作为角质细胞增殖、迁移和分化的信号。我们发现IL-24可以以IL-24受体依赖的方式替代IL-3作为小鼠IL-3依赖性前b细胞的生存和生长因子，这一发现支持了这一假设。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。我们提出以下具体目的来验证这些假设：具体目的1：通过检测IL-24是否能抑制促炎细胞因子的产生，促进细胞增殖、迁移和分化，确定IL-24对角质形成细胞的生物学功能。特异性目的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.