Sandersa Nathan L, Venkateshaiah Sathisha Upparahalli, Manohar Murli, Verma Alok K, Kandikattu Hemanth K, Mishra Anil
Department of Medicine, Tulane Eosinophilic Disorders Center, Tulane University School of Medicine, New Orleans, USA.
J Mucosal Immunol Res. 2018;2(1). Epub 2018 Jul 2.
A significant amount of correlational evidence has linked increased levels of IL-18 with allergic diseases in both human and animal models, and, as mast cells are major mediators of allergies, we hypothesized that IL-18 may have a role in mast cell biology. Rationale for our hypothesis is based on the evidence that IL-3 deficient mice are not devoid of mast cells, even though IL-3 is a major differentiation and growth factor for mast cells. Accordingly, we cultured IL-18 responsive bone marrow CD34+ cells under a variety of conditions and cytokine combinations to examine mast cell differentiation and maturation using flow cytometry, quantitative PCR,and immunostaining techniques. Additionally, mast cell transformation and maturation were also analysed using endogenous IL-18 gene-deficient or Fabpi-IL-18 overexpressed mice. Our data indicate that both IL-3 and IL-18 exposed CD34+ bone marrow precursors differentiate and mature into mast cells. Further, we observed that IL-18 differentiates mast cells independent of IL-3, as pharmacologic blockade of IL-3 does not prevent IL-18-driven mast cell differentiation. Further, we found that endogenous IL-18 deficiency restricts maturation of IL-3 generated mast cells and IL-18 derived mast cells require IL-3 for their survival. Additionally, we observed IL-18 intestinal overexpression promotes tissue mast cell proliferation and mucosal mast cell development. Taken together, we provide the evidence that IL-18 has an important contributory role in mast cell differentiation, maturation and development of mucosal mast cells. Therefore, IL-18 may represent a future pharmacologic target for treating mast cell-mediated allergic diseases.
大量的相关证据表明，在人类和动物模型中，白细胞介素-18（IL-18）水平升高与过敏性疾病有关。而且，由于肥大细胞是过敏反应的主要介质，我们推测IL-18可能在肥大细胞生物学中发挥作用。我们这一假设的依据是，尽管IL-3是肥大细胞的主要分化和生长因子，但IL-3缺陷小鼠并非没有肥大细胞。因此，我们在多种条件和细胞因子组合下培养对IL-18有反应的骨髓CD34+细胞，使用流式细胞术、定量PCR和免疫染色技术来检测肥大细胞的分化和成熟。此外，还使用内源性IL-18基因缺陷或Fabpi-IL-18过表达的小鼠分析肥大细胞的转化和成熟。我们的数据表明，暴露于IL-3和IL-18的CD34+骨髓前体细胞均可分化并成熟为肥大细胞。此外，我们观察到IL-18可独立于IL-3使肥大细胞分化，因为对IL-3的药理阻断并不能阻止IL-18驱动的肥大细胞分化。此外，我们发现内源性IL-18缺乏会限制IL-3生成的肥大细胞的成熟，而IL-18衍生的肥大细胞的存活需要IL-3。此外，我们观察到肠道中IL-18的过表达会促进组织肥大细胞增殖和黏膜肥大细胞发育。综上所述，我们提供的证据表明，IL-18在肥大细胞分化、成熟以及黏膜肥大细胞的发育中具有重要的促进作用。因此，IL-18可能是未来治疗肥大细胞介导的过敏性疾病的药物靶点。
