Pathogenesis of Fever in Humans

描述(申请人提供)：通过阻断白细胞介素1β(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，大多数会引起炎症。IL-1家族成员7(IL-1F7)的功能仍不清楚。自2000年发现以来，仅有9篇论文。在IL-1家族的所有成员中，IL-1F7和IL-18在基因组水平上关系最为密切。有报道称，caspase-1切割重组的IL-1F7前体，处理后的IL-1F7与IL-18受体结合。然而，没有令人信服的数据表明重组IL-1F7具有促炎或抗炎活性。为了避免重组形式的困难，我们将IL-1F7前体基因导入小鼠和人类细胞，观察到内毒素和IL-12诱导的促炎细胞因子受到显著抑制。抑制内源性IL-1F7会导致更高水平的促炎细胞因子。重要的是，IL-1F7转位到细胞核。因此，与IL-11和IL-33类似，IL-1F7似乎是一种“双重功能”的细胞因子，即既能在细胞核内发挥功能，又能与细胞表面受体结合。正在测试的一个假设是，IL-1F7是否与IL-18受体结合，以及这种复合体是否招募抑制性受体，即单个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-1F7的核功能是否需要SMAD3，即介导TGF2信号的细胞内蛋白。除了在细胞培养中测试这些假设外，我们还培育了一种表达人IL-1F7的小鼠。IL-1F7转基因小鼠对内毒素、葡聚糖硫酸钠结肠炎、急性心肌梗死和接触性抗原致敏的全身和局部炎症有显著的保护作用。IL-1F7现在作为一种主要的抑制性细胞因子出现，在先天性免疫反应中限制炎症。我们建议使用这些小鼠来检验每一个假说，创造三个新的小鼠品系，每个品系都表达IL-1F7，但缺乏IL-18受体、SIGIRR或SMAD3。这项提议的目的是揭示IL-1F7抗炎活性的分子要求。IL-1F7似乎填补了了解先天免疫反应如何调节的空白。

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.