IL-4 Signal Transduction

描述（由申请人提供）：细胞因子是免疫应答的重要调节剂，免疫应答是特应性哮喘和其他过敏性疾病的炎症成分的基础。白细胞介素-4是调节过敏性免疫应答的重要细胞因子。然而，调节细胞对IL-4反应的分子机制仍然没有完全确定。IL-4在B细胞生物学中起重要作用。它可以调节B细胞分化。例如，IL-4通过诱导生殖系免疫球蛋白重链转录，诱导免疫球蛋白重链类别转换为小鼠中的IgE和IgG 1（人类中的IgE和IgG 4）。它还诱导CD 23和MHC II类的表达。进一步了解IL-4介导这些生物反应的机制可能会导致治疗干预和控制过敏的新机制。为了确定IL-4激活的不同信号通路如何调节基因转录，我们通过微阵列分析鉴定了许多IL-4刺激后差异表达的基因。NFIL 3（核因子，白细胞介素3调节的）是以STAT 6依赖性方式由IL-4刺激最强烈诱导的转录因子。为了分析NFIL 3在免疫系统中的作用，我们产生了NFIL 3缺陷小鼠。NFIL 3缺陷型小鼠对抗原的反应中IgE的产生大大受损。NFIL 3缺陷型B细胞不能产生IgE，但不能产生IgG 1以响应LPS加IL-4。这些缺陷可能是由于在不存在NFIL 3的情况下，免疫球蛋白重链生殖系转录物的产生减少。此外，与野生型小鼠相比，用卵清蛋白致敏和激发的NFIL 3 KO小鼠显示出降低的气道高反应性。因此，我们假设NFIL 3是IgE产生和气道高反应性的关键调节因子。我们建议确定NFIL 3调节IgE产生和气道高反应性产生的分子机制。公共卫生相关性：白细胞介素-4是调节特应性哮喘和其他过敏性疾病的重要细胞因子。我们的申请提出研究一个白细胞介素-4诱导基因的作用，称为NFIL 3基因，似乎是小鼠过敏性免疫反应所必需的。

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. PUBLIC HEALTH RELEVANCE: Interleukin-4 is an important cytokine for the regulation of atopic asthma and other allergic diseases. Our application proposes to study the role of one Interleukin-4 -inducible gene, called NFIL3 gene, that appears to be essential for allergic immune responses in mice.