IL-4 Signal Transduction

描述(申请人提供)：细胞因子是免疫反应的重要调节剂，免疫反应是特应性哮喘和其他过敏性疾病炎症成分的基础。白介素4是调节变态反应性免疫反应的重要细胞因子。然而，调控细胞对IL-4反应的分子机制仍未完全明确。IL-4在B细胞生物学中发挥重要作用。它可以调节B细胞的分化。例如，IL-4通过诱导生殖系免疫球蛋白重链转录，在小鼠(人为IgE和IgG4)诱导免疫球蛋白重链类型转换为IgE和IgG1。它还诱导CD23和MHC-II类分子的表达。进一步了解IL-4介导这些生物反应的机制可能会为治疗干预和控制过敏提供新的机制。为了明确IL-4激活的不同信号通路如何调控基因转录，我们通过基因芯片分析鉴定了许多IL-4刺激下的差异表达基因。核因子，白介素3调节因子(NFIL3)是IL-4以STAT6依赖的方式诱导的最强转录因子。为了分析NFIL3在免疫系统中的作用，我们产生了NFIL3缺陷小鼠。NFIL3基因缺陷的小鼠对抗原的反应表现出极大的IgE产生受损。NFIL3缺陷的B细胞不能产生IgE，但不能产生IgG1，以响应内毒素和IL-4。这些缺陷可能是由于在没有NFIL3的情况下免疫球蛋白重链胚系epsilon转录本的产生减少所致。此外，与野生型小鼠相比，用卵清蛋白致敏和攻击的NFIL3 KO小鼠显示出较低的呼吸道高反应性。因此，我们假设NFIL3是IgE产生和呼吸道高反应性的关键调节因子。我们建议确定NFIL3调节IgE产生和呼吸道高反应性产生的分子机制。

DESCRIPTION (provided by applicant): Cytokines are important modulators of the immune response that underlies the inflammatory component of atopic asthma and other allergic diseases. Interleukin-4 is an important cytokine for the regulation of allergic immune responses. However, the molecular mechanisms that regulate the response of cells to IL-4 are still not completely defined. IL-4 plays an important role in B cell biology. It can regulate B cell differentiation. For example, IL-4 induces immunoglobulin heavy chain class switching to IgE and IgG1 in mice (IgE and IgG4 in humans) by inducing germline immunoglobulin heavy chain transcription. It also induces expression of CD23 and MHC class II. Further understanding of the mechanisms by which IL-4 mediates these biologic responses may lead to novel mechanisms for therapeutic intervention and control of allergy. To define how different signaling pathways activated by IL-4 regulate gene transcription, we identified many differentially expressed genes by IL-4 stimulation by microarray analysis. NFIL3 (nuclear factor, interleukin 3 regulated) is the most strongly induced transcription factor by IL-4 stimulation in a STAT6-dependent manner. To analyze the role of NFIL3 in immune system, we have generated NFIL3-deficient mice. NFIL3-deficient mice showed greatly impaired IgE production in response to antigen. NFIL3-deficient B cells fail to produce IgE but not IgG1 in response to LPS plus IL-4. These defects may be due to the reduced production of immunoglobulin heavy chain germline epsilon transcripts in the absence of NFIL3. Moreover, NFIL3 KO mice sensitized and challenged with ovalbumin showed reduced airway hyper-responsiveness when compared to wild type mice. Therefore, we hypothesize that NFIL3 is a critical regulator for IgE production and airway hyper-responsiveness. We propose to determine the molecular mechanisms by which NFIL3 regulates IgE production and the production of airway hyper-responsiveness.