Takii T
Faculty of Pharmaceutical Sciences, Nagoya City University, 3-1, Tanabe-Dori, Mizuho-ku, Nagoya 467-8603, Japan.
Yakugaku Zasshi. 2001 Jan;121(1):9-21. doi: 10.1248/yakushi.121.9.
Interleukin 1 (IL-1) is one of the inflammatory cytokines, which plays a pivotal role in both host defense and homeostasis. Its signal is transduced by type I IL-1 receptor (IL-1RI). This report gives an insight into the regulatory mechanism of IL-1RI in both in vitro and in vivo. IL-1 up-regulates IL-1RI through prostaglandin E2 (PGE2) production on human fibroblasts. However, in the presence of indomethacin, IL-1 down-regulates the receptor by destabilizing IL-1 receptor mRNA. Type I and type II interferons (IFNs) up-regulate the expression of IL-1RI. This up-regulation leads to the increasing susceptibility of IL-1RI to IL-1, as the DNA binding of IL-1-induced NF-kappa B and the production of IL-1-induced IL-6 from the fibroblasts are augmented by pretreatment with IFNs. On the other hand, the expression of cell surface IL-1RI is inhibited by tyrosine kinase inhibitors, herbimycin and genistein, resulting in reduction of the kinase activity of IRAK (IL-1 receptor associated kinase) and IL-1-induced IL-6 production from the fibroblasts. Lipopolysaccharide (LPS) augments the expression of IL-1RI mRNA and cell surface molecule in the hepatocytes of mice in vivo, and the augmentation is mediated by the interaction of IL-1, IL-6, and of glucocorticoid (GC). When hepatocytes were pretreated with dexamethasone (Dex) and IL-6, the activation of IRAK was augmented in response to IL-1, indicating that IL-1 signaling is also up-regulated. In addition, IL-1 treatment ather combined administration of Dex and IL-6 into mice markedly increased the serum level of serum amyloid A. These data suggest that the expression of IL-1RI is regulated by inflammatory cytokines, PGE2, GC and LPS in vitro and in vivo. This study shows that the biological activity of IL-1 can be controlled by regulating the expression of IL-1RI, and therefore proposes the use of pharmaceutical drugs for the regulation of cytokine expression.
白细胞介素1（IL-1）是一种炎症细胞因子，在宿主防御和体内平衡中都起着关键作用。其信号通过I型白细胞介素1受体（IL-1RI）进行转导。本报告深入探讨了IL-1RI在体外和体内的调节机制。IL-1通过人成纤维细胞产生前列腺素E2（PGE2）来上调IL-1RI。然而，在吲哚美辛存在的情况下，IL-1通过使IL-1受体mRNA不稳定来下调该受体。I型和II型干扰素（IFN）上调IL-1RI的表达。这种上调导致IL-1RI对IL-1的敏感性增加，因为用IFN预处理可增强IL-1诱导的NF-κB的DNA结合以及成纤维细胞中IL-1诱导的IL-6的产生。另一方面，酪氨酸激酶抑制剂、除莠霉素和染料木黄酮可抑制细胞表面IL-1RI的表达，导致IRAK（IL-1受体相关激酶）的激酶活性降低以及成纤维细胞中IL-1诱导的IL-6产生减少。脂多糖（LPS）可增强体内小鼠肝细胞中IL-1RI mRNA和细胞表面分子的表达，这种增强是由IL-1、IL-6和糖皮质激素（GC）的相互作用介导的。当用 dexamethasone（Dex）和IL-6预处理肝细胞时，对IL-1的反应中IRAK的激活增强，表明IL-1信号传导也被上调。此外，对小鼠进行IL-1处理或联合给予Dex和IL-6可显著提高血清淀粉样蛋白A的血清水平。这些数据表明，IL-1RI的表达在体外和体内受到炎症细胞因子、PGE2、GC和LPS的调节。本研究表明，可通过调节IL-1RI的表达来控制IL-1的生物学活性，因此提出使用药物来调节细胞因子的表达。
