Document Detail


Attenuation of interleukin-8 production by inhibiting nuclear factor-kappaB translocation using decoy oligonucleotides.
MedLine Citation:
PMID:  10677576     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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-kappaB (NF-kappaB), a family of proteins that is important in the transcriptional control of a number of genes. When cells are activated, NF-kappaB 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-kappaB 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-kappaB binds within the IL-8 gene. We then investigated the effects of transfection of monocytes with these oligonucleotides on interleukin-1beta (IL-1beta)-stimulated IL-8 production, IL-8 mRNA expression, and NF-kappaB 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-kappaB-binding sequence was the most potent of those tested. This single-stranded oligonucleotide also inhibited IL-1beta-induced translocation of NF-kappaB 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.
Authors:
J A Cooper; J M Parks; R Carcelen; S S Kahlon; M Sheffield; R Culbreth
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Biochemical pharmacology     Volume:  59     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2000 Mar 
Date Detail:
Created Date:  2000-03-03     Completed Date:  2000-03-03     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  605-13     Citation Subset:  IM    
Affiliation:
Pulmonary Sections, Birmingham Veterans Affairs Medical Center, Birmingham, AL 35233, USA.
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MeSH Terms
Descriptor/Qualifier:
Binding, Competitive
Biological Transport / drug effects
Cell Survival / drug effects
Consensus Sequence
Humans
Interleukin-8 / biosynthesis*,  metabolism
Monocytes / drug effects,  metabolism
NF-kappa B / drug effects,  genetics,  metabolism*
Oligonucleotides / genetics,  pharmacology*
Phosphatidylethanolamines / pharmacology
Protein Binding
RNA, Messenger / metabolism
Subcellular Fractions
Transfection
Chemical
Reg. No./Substance:
0/Interleukin-8; 0/NF-kappa B; 0/Oligonucleotides; 0/Phosphatidylethanolamines; 0/RNA, Messenger; 76391-83-8/1,2-dielaidoylphosphatidylethanolamine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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