TRANSLATIONAL CONTROL OF THE ACUTE PHASE RESPONSE

巨噬细胞衍生细胞因子的炎症信号，如IL-1β， IL-6和肿瘤坏死因子在急性期重新编程肝脏基因转录 响应(APR)。然而，肝H-和L的翻译效率- 铁蛋白mRNAs(H-和L-mRNAs)也随着IL-1β的增加而增加 信使核糖核酸水平没有变化。这表明炎症性疾病 细胞因子可能不仅传递刺激增加的信号 APR基因转录，但也通过改变mRNA来改变基因表达 翻译。增加铁蛋白的翻译和积累将 增加组织的铁存储容量，并从血清中去除铁。 这可能会在APR期间产生保护性反应。的抄写 典型的人类肝脏APR基因，如血清淀粉样蛋白A(SAA)和α-1 酸性糖蛋白(AGP)在暴露于炎性细胞因子后增加。 然而，肝脏SAA和AGP基因的表达也受到后 它们以稳定的mRNAs形式出现后的转录机制 细胞质。这些蛋白质被翻译并作为另一部分输出 一种适应性反应，以最大限度地减少炎症期间的损害。以下是 计划进行实验： A)研究IL-1β、肿瘤坏死因子和IL-6在H-和L铁蛋白中的作用 肝癌细胞(HepG2和Hep3B)及血管内皮细胞的基因翻译 B)分析在以下方面影响翻译控制的机制 急性期反应。铁蛋白mRNAs中的RNA序列 将评估对IL-1β、肿瘤坏死因子和IL-6的翻译反应。核糖核酸 H-和L基因5‘非编码区序列 与其他APR基因5‘非编码区的基序相似，包括 AGP。翻译调节可能通过这样的方式发挥作用的假设 将对“RNA增强剂”进行测试。 C)Poly(A)尾巴在肝脏mRNAs的3‘端延长或缩短 4月这对AGP、SAA、铁蛋白翻译和RNA的影响 暴露在细胞因子下的肝癌细胞的稳定性将是其特征。

Inflammatory signals from macrophage derived cytokines such as Il-1beta, Il-6, and TNF reprogram liver gene transcription during the acute phase response (APR). However the translational efficiency of hepatic H- and L- ferritin mRNAs (H- and L-mRNAs) also increases in response to Il-1beta in the absence of changes in mRNA levels. This suggests that inflammatory cytokines may not only transduce signals which stimulate increased transcription of APR genes but also change gene expression by altering mRNA translation. Increased translation and accumulation of ferritin would increase the iron storage capacity of tissues, and remove iron from serum. This may afford a protective response during the APR. The transcription of typical human liver APR genes such as serum amyloid A (SAA) and alpha-1 acid glycoprotein (AGP) increases after exposure to inflammatory cytokines. However liver SAA and AGP gene expression is also controlled by post- transcriptional mechanisms after their appearance as stable mRNAs in the cytoplasm. These proteins are translated and exported as another part of an adaptive response to minimize damage during inflammation. The following experiments are planned: A)An examination of the role of Il-1beta, TNF, & Il-6 in H- & L- ferritin gene translation in hepatoma (HepG2 & Hep3B) and endothelial cells. B)An analysis of the mechanisms influencing translational control during the acute phase response. The RNA sequences in ferritin mRNAs which are translationally responsive to Il-1beta, TNF and Il-6 will be assessed. RNA elements in the 5' non coding regions of H- and L- mRNA exhibit sequence similarity with a motif in other APR gene 5' noncoding regions, including AGP. The hypothesis that translational regulation might act through such "RNA enhancers" will be tested. C)Poly(A) tails lengthen or shorten at the 3' of liver mRNAs during the APR. The effect of this on AGP, SAA, and ferritin translation and RNA stability will be characterized in hepatoma cells exposed to cytokines.