CNI-1493 inhibits monocyte/macrophage tumor necrosis factor by suppression of translation efficiency
CNI-1493 inhibits monocyte/macrophage tumor necrosis factor by suppression of translation efficiency
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DOI：
10.1073/pnas.93.9.3967
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发表时间：
1996-04-30
影响因子：
11.1
通讯作者：
Tracey, KJ
中科院分区：
文献类型：
--
作者：
Cohen, PS;Nakshatri, H;Tracey, KJ
肿瘤坏死因子（TNF）介导多种疾病状态，包括感染性休克、急慢性炎症和恶病质。最近，一种多价鸟酰脲（CNI-1493）作为巨噬细胞激活的抑制剂被证明可以抑制TNF的产生，并保护机体免受组织炎症和内毒素的伤害[Bianchi， M., Ulrich， P., Bloom， O., Meistrell， M., Zimmerman， G.A., Schmidtmayerova， H., Bukrinsky， M., Donnelley， T., Bucala， R., Sherry， B., Manogue， K. R., Tortolani, a .J., Cerami, a .和Tracey， K.J.(1995)]。与Bianchi， M, Bloom， O., Raabe， T., Cohen， P. S., Chesney， J., Sherry， B., Schmidtmayerova， H., Zhang， X., Bukrinsky， M., Ulrich， P., Cerami， A.和Tracey， J. (1996) J. Exp. Med., in press]。我们现在已经阐明了CNI-1493抑制巨噬细胞TNF合成的机制，并在这里表明它通过抑制TNF翻译效率起作用。CNI-1493既不阻断脂多糖（LPS）诱导的TNF mRNA表达的增加，也不阻断核因子NF-kappa B在LPS刺激15分钟后活化的巨噬细胞向核的易位，表明CNI-1493不干扰NF-kappa B介导的TNF的早期转录调节。然而，CNI-1493有效阻断了26 kda膜形式TNF的合成。使用含有TNF基因中参与TNF翻译调节的元件的氯霉素乙酰转移酶（CAT）构建体进行实验，进一步证明了TNF的翻译抑制作用。TNF基因的5‘和3’非翻译区都需要引起CNI-1493的最大翻译抑制。确定CNI-1493抑制TNF翻译的分子靶点，有助于深入了解巨噬细胞活化的调控和炎症的机制。
Tumor necrosis factor (TNF) mediates a wide variety of disease states including septic shock, acute and chronic inflammation, and cachexia. Recently, a multivalent guanylhydrazone (CNI-1493) developed as an inhibitor of macrophage activation was shown to suppress TNF production and protect against tissue inflammation and endotoxin lethality [Bianchi, M., Ulrich, P., Bloom, O., Meistrell, M., Zimmerman, G.A., Schmidtmayerova, H., Bukrinsky, M., Donnelley, T., Bucala, R., Sherry, B., Manogue, K. R., Tortolani, A. J., Cerami, A. & Tracey, K.J. (1995) Mel. Med. 1, 254-266, and Bianchi, M., Bloom, O., Raabe, T., Cohen, P. S., Chesney, J., Sherry, B., Schmidtmayerova, H., Zhang, X., Bukrinsky, M., Ulrich, P., Cerami, A. & Tracey, J. (1996) J. Exp. Med., in press]. We have now elucidated the mechanism by which CNI-1493 inhibits macrophage TNF synthesis and show here that it acts through suppression of TNF translation efficiency. CNI-1493 blocked neither the lipopolysaccharide (LPS)-induced increases in the expression of TNF mRNA nor the translocation of nuclear factor NF-kappa B to the nucleus in macrophages activated by 15 min of LPS stimulation, indicating that CNI-1493 does not interfere with early NF-kappa B-mediated transcriptional regulation of TNF. However, synthesis of the 26-kDa membrane form of TNF was effectively blocked by CNI-1493. Further evidence for the translational suppression of TNF is given by experiments using chloramphenicol acetyltransferase (CAT) constructs containing elements of the TNF gene that are involved in TNF translational regulation. Both the 5' and 3' untranslated regions of the TNF gene were required to elicit maximal translational suppression by CNI-1493. Identification of the molecular target through which CNI-1493 inhibits TNF translation should provide insight into the regulation of macrophage activation and mechanisms of inflammation.