Study on the interleukin-1 signaling

以人黑色素瘤细胞A375为研究对象，研究了il -增殖作用的机制及获得性抵抗IL-1作用的机制。I型IL-1受体（type IL-1 receptor, IL-1R）是IL-1信号的转导者，我们也研究了IL-1R在体外和体内表达的调控机制。将IL-1抗增殖的有效性- 1r cDNA转染到对IL-1具有抗性的A375-5中，其IL-1R表达量极低。我们获得了对IL-1敏感的转染物。利用这个克隆，我们研究了IL-1信号。IL-1下调ODC活性。虽然ODC mRNA水平未发生变化，但ODC蛋白含量下降。抗酶（AZ）是一种通过与ODC结合而使ODC失活并导致ODC降解的蛋白质因子，其mRNA被IL-1上调。此外，反义AZ抑制IL-1的作用。因此，IL-1诱导的AZ似乎在IL-1信号传导中起重要作用。利用经长期培养获得IL-1抗增殖作用的细胞，对其机制进行了研究。将IL-1alpha正义表达载体和IL-1alpha反义表达载体分别转染到IL-1敏感和耐药细胞中。然而，转染物对IL-1的敏感性没有改变。因此，il -1 α的表达似乎不足以抵抗。我们利用人成纤维细胞系TIG-1，研究I型IL-1R表达的调控机制。酪氨酸激酶似乎在IL-1R的组成表达中起重要作用。注射LPS后，小鼠肝脏IL-1R mRNA水平明显升高。这种上调似乎是由内源性产生的IL-1和IL-6诱导的。

The mechanisms of IL-latiproliferative effect and the acquired resistance to IL-1 effect were studied using human melanoma cells A375. As type I IL-1 receptor (IL-1R) transduces IL-1 signal, the regulatory mechanisms of IL-1R expression in vitro and in vivo were also studied.1. The mechanism of IL-1 antiproliferative effectIL-1R cDNA was transfected into A375-5 which is resistant to IL-1 because it expresses very low number of IL-1R.We obtained the transfectant which became sensitive to IL-1. Using this clone we studied the IL-1 signaling. IL-1 downregulated ODC activity. Although ODC mRNA level was not changed, the amount of protein of ODC decreased. The mRNA of antizyme (AZ), a proteinous factor which inactivates ODC by binding to ODC and causes degradation of ODC,was upregulated by IL-1. Furthermore, antisense of AZ inhibited IL-1 effects. Terefore, AZ induced by IL-1 appeared to be important in the IL-1 signaling.2. The mechanism of acquired resistance to IL-1Using the cells which acquired resistance to IL-1 antiproliferative effect after long period of culture, we studied the mechanism. Expression vectors of IL-1alpha sense and IL-1alpha antisense were transfected into IL-1 sensitive and resistant cells, respectively. However, the sensitivity of the transfectants to IL-1 was not changed. Therefore, expression of IL-1alpha appeared not to be sufficient to the resistance.3. Regulation of IL-1R expressionUsing human fibroblast cell line TIG-1, we studied the regulatory mechanism of type I IL-1R wxpression. Tyrosine kinase appeared to play an important role in constitutive expression of IL-1R.Whtn mice were injected with LPS,a marked increase of IL-1R mRNA was induced in the liver. The upregulation apperaed to be induced by the endogenously produced IL-1 and IL-6.