Transcriptional regulation of Toll-like receptor signaling

性状（由申请人提供）：Toll样受体（TLR）是微生物产物的关键传感器，对病原体先天免疫的发展至关重要。TLR激活诱导数百种编码炎性细胞因子、抗微生物蛋白以及再生和代谢调节因子的基因的表达;这些分子反过来介导感染性疾病患者中观察到的炎症、抗微生物免疫和组织再生。然而，TLR的不受控制或延长的激活可具有破坏性后果，其包括脓毒性休克和致命的炎性疾病的发展。幸运的是，TLR激活受到两类负调控因子的严格控制：a）抑制TLR信号传导的信号特异性调控因子，和B）抑制TLR靶基因转录的基因特异性调控因子。这些调节剂确保TLR长期或重复暴露于其配体不会导致受体的持续激活;相反，它使它们对随后的配体刺激不敏感或低反应。这种现象被称为TLR耐受性，或当LPS是所涉及的配体时的脂多糖（LPS）耐受性。最近的LPS应答基因组分析揭示LPS耐受性是一种基因特异性现象，即，它选择性地靶向一组基因（例如，炎性基因）而不是其它（例如，事实上，在LPS耐受的细胞中，抗微生物基因的表达进一步上调。因为是炎症基因而不是抗菌基因引起有害的炎症反应，所以LPS耐受性确保宿主能够持续建立其抗菌免疫力，而不会引起致命的炎症性疾病，即使是慢性或长期感染。然而，长时间的LPS暴露激活抗菌基因，但矛盾地抑制炎症基因的分子机制是未知的。我们最近发现B细胞白血病（Bcl）-3通过抑制核因子（NF）-κ B（LPS激活的三种主要转录因子之一）介导LPS耐受。本研究的目的是阐明Bcl-3调节TLR激活和耐受的分子机制。具体而言，我们将定义1）基因启动子的NF-κ B结合位点在TLR耐受中的作用，2）TLR信号传导中p50泛素化的作用，以及3）Bcl-3抑制p50泛素化的机制。从这些研究中产生的信息不仅可能带来TLR信号传导机制方面的重要概念进展，而且还有助于开发新的基于Bcl-3的感染性疾病治疗策略。

DESCRIPTION (provided by applicant): Toll-like receptors (TLRs) are key sensors of microbial products and are essential for the development of innate immunity to pathogens. TLR activation induces the expression of hundreds of genes that encode inflammatory cytokines, antimicrobial proteins, and regeneration and metabolic regulators; these molecules in turn mediate inflammation, antimicrobial immunity and tissue regeneration seen in patients with infectious diseases. However, uncontrolled or prolonged activation of TLRs can have devastating consequences, which include the development of septic shock and fatal inflammatory diseases. Fortunately, TLR activation is tightly controlled by two classes of negative regulators: a) signal-specific regulators that inhibit TLR signaling, and b) gene-specific regulators that suppress TLR target gene transcription. These regulators ensure that prolonged or repeated exposure of TLRs to their ligands does not lead to sustained activation of the receptors; instead, it renders them insensitive or hyporesponsive to subsequent ligand stimulation. This phenomenon is referred to as TLR tolerance, or lipopolysaccharide (LPS) tolerance when LPS is the ligand involved. Recent genomic profiling of LPS responses reveals that LPS tolerance is a gene-specific phenomenon, i.e., it selectively targets one set of genes (e.g., inflammatory genes) but not others (e.g., antimicrobial genes); in fact, the expression of antimicrobial genes is further upregulated in LPS tolerized cells. Because it is the inflammatory genes, not the antimicrobial genes, that cause deleterious inflammatory responses, LPS tolerance ensures that the host is able to continuously build up its antimicrobial immunity without causing fatal inflammatory diseases even with chronic or prolonged infections. However, the molecular mechanisms through which prolonged LPS exposure activates antimicrobial genes, but paradoxically suppresses inflammatory genes are unknown. We recently discovered that B cell leukemia (Bcl)-3 mediates LPS tolerance by inhibiting nuclear factor (NF)-kB, one of the three major transcription factors activated by LPS. The goal of this investigation is to elucidate the molecular mechanisms through which Bcl-3 regulates TLR activation and tolerance. Specifically, we will define 1) the roles of NF-kB binding sites of gene promoters in TLR tolerance, 2) the roles of p50 ubiquitination in TLR signaling, and 3) the mechanisms through which Bcl-3 inhibits p50 ubiquitination. Information generated from these studies may not only bring about an important conceptual advance with regard to mechanisms of TLR signaling but also aid in the development of novel Bcl-3-based strategies for the treatment of infectious diseases.