Role of meteorin-like in the immune system

通过对基因表达综合数据库（Body Index of Gene）的生物信息学分析， 表达（BIGE）），我们试图鉴定与免疫系统相关的新的/未表征的基因。 我们鉴定了一种由激活的巨噬细胞表达的特征不明显的分泌蛋白， 目前被鉴定为"类流星体"（meternl）。该基因在屏障组织（皮肤、粘膜）中强烈表达 以及被激活的巨噬细胞所吞噬Metrnl编码一个311个氨基酸的小分泌蛋白， 氨基酸信号肽，预测266个氨基酸的成熟蛋白质，具有估计的分子量 约29KDa。它在人外周血单核细胞或小鼠腹腔巨噬细胞中表达， 活化，并且其表达由各种细胞因子调节（正或负）。我们已经生产 Metrnl/IL-39-/-小鼠，其存活并繁殖良好，但表现出各种免疫系统缺陷。采取 总之，我们得出结论，Metrnl代表了一种新的细胞因子，我们建议将其命名为白细胞介素 39（IL-39）。Metrnl/IL-39在银屑病和类风湿性关节炎中过表达，表明其在人类中的作用。 炎症/自身免疫性疾病。Metrnl/IL-39的表达也在注射Metrnl/IL-39的小鼠的腹膜中被诱导。 与巯基乙酸盐有关，这与其在炎症中的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IgG水平，这是由于非常低的IgG2b水平， IgG 3。此外，其脾细胞表现出改变的细胞因子产生，包括不能产生一些细胞因子。 趋化因子（CCL3）以及显著较低水平的IFN γ。这些观察结果有力地支持了我们的 结论Metrn1/IL-39是一种新的免疫调节细胞因子。Metrnl/IL-39已被 据报道，诱导核受体PPAR γ在脂肪细胞中的表达，但它对细胞的影响， 免疫系统未知。在具体目标1中，我们将鉴定免疫系统中表达 基于Metrnl/IL-39诱导PPAR γ表达或结合PPAR γ的能力， 生物素化的Metrnl/IL-39（通过FACS检测）。我们还将探讨是否B细胞缺陷中观察到的， Metrnl/IL-39-/-小鼠（非常低的IgG 2 B b和IgG 3）是由于B细胞中有缺陷的类别转换，并将探索 Metrnl/IL-39在幼稚T细胞向Th1、Th2、Th17和iTreg阶段极化中的潜在作用。我们 还观察到Metrnl/IL-39-/-小鼠对刚地弓形虫高度易感。具体目标 2，我们将探讨几种免疫机制，可能占这种增加的易感性T。刚地。 我们将研究弓形虫在来自Metrnl/IL-39或野生型（WT）小鼠的单核细胞中生长的能力， 还将监测感染期间Metrnl/IL-39-/-或WT小鼠中的Thl、Th2或Thl7细胞因子水平。我们将最终 确定Metrnl/IL-39的施用是否可以逆转在Metrnl/IL-39-/-小鼠中观察到的易感性。 小鼠为T.刚地。通过这些研究，我们将验证Metrnl/IL-39代表一种新的免疫调节剂的假设。 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。

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.