Pathogenesis of Fever in Humans

描述（由申请人提供）：通过阻断白细胞介素-1 β（IL-12）活性治疗急性和慢性炎症性疾病现在是临床实践的一部分。IL-1家族有11个成员，大多数诱导炎症。其中一个成员，IL-1家族成员7（IL-1F 7）的功能仍然难以捉摸。自2000年发现以来，只有9篇论文。在IL-1家族的所有成员中，IL-1F 7和IL-18在基因组水平上最密切相关。有一份报告称，胱天蛋白酶-1切割重组IL-1F 7前体，并且经加工的IL-1F 7与IL-18受体结合。然而，没有令人信服的数据表明重组IL-1F 7表现出促炎或抗炎活性。为了避免重组形式的困难，我们将IL-1F 7前体转染到小鼠和人细胞中，并观察到对内毒素和IL-12诱导的促炎细胞因子的显著抑制。内源性IL-1F 7的沉默导致更高水平的促炎细胞因子。重要的是，IL-1F 7易位到细胞核。因此，与IL-11和IL-33类似，IL-1F 7似乎是一种“双重功能”细胞因子，即在细胞核中起作用以及与细胞表面受体结合。一个正在测试的假设是IL-1F 7是否与IL-18受体结合，以及这种复合物是否募集抑制性受体，单一IG IL-1相关受体（SIGIRR）来抑制细胞因子。另一个正在测试的假设是IL-1F 7的核功能是否需要Smad 3，即介导TGF 2信号传导的细胞内蛋白。除了在细胞培养物中测试这些假设之外，我们还产生了表达人IL-1F 7的小鼠品系。IL-1F 7转基因小鼠对内毒素、葡聚糖硫酸钠结肠炎、急性心肌缺血性梗死和接触抗原致敏的全身和局部炎症具有显著的保护作用。IL-1F 7现在作为一种主要的抑制性细胞因子出现，在先天免疫应答期间限制炎症。我们建议使用这些小鼠来测试每一个假设，通过创建三个新的小鼠品系，每个小鼠表达IL-1F 7，但缺乏IL-18受体，SIGIRR或Smad 3。该提案的目标是揭示IL-1F 7抗炎活性的分子要求。IL-1F 7似乎填补了理解先天免疫反应如何调节的空白。 公共卫生相关性：该项目的相关性是人类疾病之一，其中炎症起着重要的作用。许多炎症是由称为细胞因子的小蛋白质分子引发的，这些细胞因子刺激引起炎症的基因。该项目旨在了解细胞因子引起的炎症是如何控制的。这些信息将导致更好地了解疾病的严重程度，并可能导致新的抗炎治疗。

DESCRIPTION (provided by applicant): Treating acute and chronic inflammatory diseases by blocking interleukin-1 beta (IL-12) activity is now part of clinical practice. There are 11 members of the IL-1 family and most induce inflammation. The function of one member, IL-1 family member 7 (IL-1F7), remains elusive. Since its discovery in 2000, there are only 9 papers. Of all members of the IL-1 family, IL-1F7 and IL-18 are the most closely related at the genomic level. There is one report that caspase-1 cleaves the recombinant IL-1F7 precursor and that processed IL-1F7 binds to the IL-18 receptor. However, there is no convincing data that recombinant IL-1F7 exhibits either pro- or anti- inflammatory activities. To avoid difficulties with recombinant forms, we transfected the IL-1F7 precursor into mouse and human cells and observed a profound suppression of endotoxin- and IL-12-induced pro- inflammatory cytokines. Silencing of endogenous IL-1F7 results in higher levels of pro-inflammatory cytokines. Importantly, IL-1F7 translocates to the nucleus. Thus, similar to IL-11 and IL-33, IL-1F7 appears to be a "dual function" cytokine, that is, functional in the nucleus as well as binding to a cell surface receptor. One hypothesis being tested is whether IL-1F7 binds to the IL-18 receptor and whether such a complex recruits the inhibitory receptor, Single Ig IL-1 Related Receptor (SIGIRR) to suppress cytokines. Another hypothesis being tested is whether the nuclear function of IL-1F7 requires Smad3, the intracellular protein that mediates TGF2 signaling. In addition to testing these hypotheses in cell cultures, we have generated a strain of mice that express human IL-1F7. IL-1F7 transgenic mice are significantly protected against the systemic and local inflammation of endotoxin, dextran sodium sulfate colitis, acute myocardial ischemic infarction and contact antigen sensitization. IL-1F7 now emerges as a major inhibitory cytokine that limits inflammation during innate immune responses. We propose to use these mice to test each of the hypotheses by creating three new strains of mice, each expressing IL-1F7 but deficient in either the IL-18 receptor, SIGIRR or Smad3. The goal of this proposal is to reveal the molecular requirements for the anti-inflammatory activity of IL-1F7. IL-1F7 appears to fill a gap in understanding how the innate immune response is regulated. PUBLIC HEALTH RELEVANCE: The relevance of the project is one of human disease in which inflammation plays an important component. Much of inflammation is triggered by small protein molecules called cytokines that act to stimulate genes that cause inflammation. The project seeks to understand how inflammation caused by cytokines is controlled. This information will result in a better understanding of disease severity and possibly new anti-inflammatory therapies.