Attenuation of interleukin-8 production by inhibiting nuclear factor-κB translocation using decoy oligonucleotides

被引:35
作者
Cooper, JAD [1 ]
Parks, JM
Carcelen, R
Kahlon, SS
Sheffield, M
Culbreth, R
机构
[1] Univ Alabama, Div Pulm & Crit Care Med, Univ Stn, Birmingham, AL 35294 USA
[2] Vet Adm Med Ctr, Pulm Sect, Birmingham, AL 35233 USA
关键词
inflammation; interleukin-8; NF kappa B; monocytes; oligonucleotides; northern blotting;
D O I
10.1016/S0006-2952(99)00375-5
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Interleukin-8 (IL-8), a monocyte-derived neutrophil chemoattractant factor, is a polymorphonuclear neutrophil chemotaxin that is involved in a number of inflammatory disorders. Transcription of the IL-8 gene is controlled by regulatory proteins, including nuclear factor-kappa B (NF kappa B), a family of proteins that is important in the transcriptional control of a number of genes. When cells are activated, NF-kappa B translocates from the cytoplasm to the nucleus, where it activates transcription by binding to a specific sequence within the 5' untranslated region of the gene. During translocation, NF-kappa B is potentially susceptible to diversion by oligonucleotides that contain the binding sequence for this protein. In the current study, we produced phosphorothioate-modified oligonucleotides containing the specific DNA sequence that NF-kappa B binds within the IL-8 gene. We then investigated the effects of transfection of monocytes with these oligonucleotides on interleukin-1 beta (IL-1 beta)-stimulated IL-8 production IL-8 mRNA expression, and NF-kappa B binding activity. We found that transfection with these oligonucleotides significantly inhibited monocyte IL-8 production. A single-stranded oligonucleotide with two copies of the NF-kappa B-binding sequence was the most potent of those tested. This single-stranded oligonucleotide also inhibited IL-1 beta-induced translocation of NF-kappa B to the nucleus and reduced IL-8 mRNA expression. These studies demonstrated that monocyte production of IL-8 can be attenuated using a single-stranded oligonucleotide that binds a transcriptional activating protein before it translocates to the cell nucleus. This approach ultimately may be useful in the control of inflammation involved in a number of diseases. (C) 2000 Elsevier Science Inc.
引用
收藏
页码:605 / 613
页数:9
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