Role of meteorin-like in the immune system

陨石蛋白样在免疫系统中的作用

• 批准号: 9398097
• 负责人: Albert Zlotnik
• 金额: $ 18.41万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-13 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9398097
• 关键词: Adipocytes; Adipose tissue; Amino Acids; Antiinflammatory Effect; Autoimmune Diseases; B-Lymphocytes; Binding; Bioinformatics; Biological; Biology; Biotin; CCL3 gene; Cells; Data; Databases; Defect; Exercise; Exhibits; Flow Cytometry; Gene Expression; Genes; Human; Human body; IgG3; Immune; Immune response; Immune system; Immunity; Immunoglobulin Class Switching; Immunoglobulin G; In Vitro; Infection; Inflammation; Inflammatory; Integral Membrane Protein; Interferons; Interleukin-4; Interleukin-6; Interleukins; Label; Leukocytes; Link; Lymphocyte; Metabolic; Molecular Weight; Monitor; Mucous Membrane; Mus; Muscle; Names; Natural Immunity; Nuclear Receptors; Pathogenesis; Pathway interactions; Pattern; Peptide Signal Sequences; Peritoneal Macrophages; Peritoneum; Peroxisome Proliferator-Activated Receptors; Phenotype; Physiological; Play; Predisposition; Production; Proteins; Psoriasis; Recombinants; Regulatory T-Lymphocyte; Reporting; Research; Rheumatoid Arthritis; Role; Sepsis; Serum; Skin; Splenocyte; System; T-Lymphocyte; TNF gene; Thioglycolates; Tissues; Toxoplasma; Toxoplasma gondii; Wild Type Mouse; acquired immunity; base; chemokine; cytokine; human genome sequencing; immunoregulation; in vivo; indexing; macrophage; monocyte; novel; overexpression; peripheral blood; receptor

Through bioinformatics analyses of a comprehensive database of gene expression (Body Index of Gene Expression (BIGE)), we sought to identify novel/uncharacterized genes associated with the immune system. We identified a poorly characterized secreted protein expressed by activated macrophages encoded by a gene currently identified as ‘meteorin-like’ (metrnl). This gene is strongly expressed in barrier tissues (skin, mucosa) and by activated macrophages. Metrnl encodes a small secreted protein of 311 aminoacids with a 45 aminoacid signal peptide, predicting a mature protein of 266 aminoacids, with an estimated molecular weight of ~29KDa. It is expressed in human peripheral blood monocytes or mouse peritoneal macrophages following activation and its expression is modulated (positively or negatively) by various cytokines. We have produced a Metrnl/IL-39-/- mouse which is viable and breeds well, but exhibits various immune system defects. Taken together, we conclude that Metrnl represents a novel cytokine for which we recommend the name interleukin 39 (IL-39). Metrnl/IL-39 is overexpressed in psoriasis and rheumatoid arthritis, suggesting a role in human inflammatory/autoimmune diseases. Metrnl/IL-39 expression is also induced in the peritoneum of mice injected with thioglycollate, consistent with a role in inflammation. The immune system abnormalities we have detected in the Metrnl/Il-39-/- mouse, include lower serum IgG levels, which are due to very low levels of IgG2b and IgG3. Furthermore, its splenocytes exhibit altered cytokine production, including inability to produce some chemokines (CCL3) as well as significantly lower levels of IFN. These observations strongly support our conclusion that Metrnl/IL-39 represents a novel cytokine involved in immunoregulation. Metrnl/IL-39 has been reported to induce the expression of the nuclear receptor PPAR in adipocytes, but its effects on cells of the immune system are unknown. In Specific Aim 1, we will identify cells of the immune system that express the Metrnl/IL-39 receptor based on the ability of Metrnl/IL-39 to induce the expression of PPAR, or to bind biotinylated Metrnl/IL-39 (detected by FACS). We will also explore whether the B cell defects observed in the Metrnl/IL-39-/- mouse (very low IgG2b and IgG3) are due to defective class switching in B cells, and will explore a potential role for Metrnl/IL-39 in the polarization of naïve T cells to the Th1, Th2, Th17 and iTreg stages. We have also observed that the Metrnl/IL-39-/- mouse is highly susceptible to Toxoplasma gondii. In Specific Aim 2, we will explore several immune mechanisms that may account for this increased susceptibility to T. gondii. We will study the ability of Toxoplasma to grow in monocytes from Metrnl/IL-39 or wild type (WT) mice, and will also monitor Th1, Th2 or Th17 cytokine levels in Metrnl/IL-39-/- or WT mice during infection. We will finally determine whether administration of Metrnl/IL-39 can reverse the susceptibility observed in the Metrnl/IL-39-/- mouse to T. gondii. Through these studies we will validate the hypothesis that Metrnl/IL-39 represents a novel cytokine associated with the immune system and inflammation and will open a new field of research.

通过对基因表达综合数据库(基因身体指数)的生物信息学分析 表达(BigE))，我们试图识别与免疫系统相关的新的/未鉴定的基因。 我们发现了一种由激活的巨噬细胞表达的分泌蛋白，该蛋白由一种基因编码 目前已被鉴定为“类陨星”(Metrnl)。该基因在屏障组织(皮肤、粘膜)中强烈表达。 和被激活的巨噬细胞。Metrn1编码一种由311个氨基酸组成的分泌蛋白，编码45个氨基酸。 氨基酸信号肽，预测一个由266个氨基酸组成的成熟蛋白质，估计其相对分子质量 大约29 KDa。它在人外周血单核细胞或小鼠腹膜巨噬细胞中表达 激活及其表达受各种细胞因子的调节(正向或负向)。我们已经制作了 Metrnl/IL-39-/-小鼠是一种活的，繁殖良好，但表现出各种免疫系统缺陷的小鼠。已被占用 总之，我们得出结论，Metrnl代表一种新的细胞因子，我们推荐将其命名为IL 39(IL-39)。Metrn1/IL-39在银屑病和类风湿关节炎中过表达，提示在人类 炎症性/自身免疫性疾病。注射的小鼠腹膜中也可诱导Metrn1/IL-39的表达 含有硫代乙醇酸盐，与炎症作用一致。我们检测到的免疫系统异常 在Metrnl/Il-39-/-小鼠中，包括较低的血清免疫球蛋白水平，这是由于非常低的IgG2b和 IgG3。此外，它的脾细胞表现出细胞因子产生的改变，包括不能产生一些 趋化因子(CCl_3)和干扰素水平显著降低。这些观察结果有力地支持了我们的 结论Metrnl/IL-39是一种参与免疫调节的新细胞因子。Metrnl/IL-39已经 据报道可诱导脂肪细胞核受体PPAR的表达，但其对细胞的影响 免疫系统是未知的。在特定的目标1中，我们将识别免疫系统中表达 基于Metrn1/IL-39受体诱导PPAR表达或结合能力的研究 生物素标记的Metrnl/IL-39(FACS检测)。我们还将探索在B细胞缺陷中观察到的 Metrnl/IL-39-/-小鼠(非常低的IgG2b和IgG3)是由于B细胞类转换缺陷所致，并将探索 Metrn1/IL-39在初始T细胞向Th1、Th2、Th17和iTreg阶段极化中的潜在作用我们 也观察到Metrnl/IL-39-/-小鼠对弓形虫高度敏感。以特定的目标 2，我们将探索几种可能解释弓形虫易感性增加的免疫机制。 我们将研究弓形虫在Metrnl/IL-39或野生型(WT)小鼠单核细胞中的生长能力，以及 还将监测感染期间Metrnl/IL-39-/-或WT小鼠的Th1、Th2或Th17细胞因子水平。我们最终会 确定给予Metrnl/IL-39是否可以逆转Metrnl/IL-39-/-的敏感性 老鼠对弓形虫的感染。通过这些研究，我们将验证Metrnl/IL-39代表一种新的 细胞因子与免疫系统和炎症相关，将开辟一个新的研究领域。