PMID- 10657660
OWN - NLM
STAT- MEDLINE
DCOM- 20000309
LR  - 20190515
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 164
IP  - 4
DP  - 2000 Feb 15
TI  - Selective inhibition of monocyte chemoattractant protein-1 gene expression in 
      human embryonal kidney cells by specific triple helix-forming oligonucleotides.
PG  - 2070-6
AB  - Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that is expressed by a 
      variety of tissue cells in response to inflammatory stimuli, such as IL-1beta, 
      TNF-alpha, and IFN-gamma. A major function of MCP-1 is the recruitment and 
      activation of monocytes and T lymphocytes. Overexpression of MCP-1 has been 
      implicated in a number of diseases, including glomerulonephritis and rheumatoid 
      arthritis, indicating that the modulation of MCP-1 activity and/or expression is 
      a desired therapeutic strategy. In the present study, our aim was to test whether 
      the MCP-1 expression could be inhibited at the transcriptional level using triple 
      helix-forming oligonucleotides (TFOs). We designed a TFO targeted to the SP-1 
      binding site in the human MCP-1 gene promoter. Gel mobility shift assays 
      demonstrated that the phosphodiester TFO formed a sequence-specific triplex with 
      its dsDNA target with an EC50 of approximately 1.9 x 10(-7) M. The corresponding 
      phosphorothioated oligonucleotide was also effective in this assay with an 8-fold 
      higher EC50 value. Binding of the TFO to the target DNA prevented the binding of 
      rSP-1 and of nuclear proteins in vitro. The TFO could also partially inhibit 
      endogenous MCP-1 gene expression in cultured human embryonic kidney cells. 
      Treatment of TNF-alpha-stimulated human embryonic kidney 293 cells with the TFO 
      inhibited the secretion of MCP-1 in a dose-dependent manner (up to 45% at 5 
      microM oligonucleotide). The inhibition of MCP secretion was caused at the level 
      of gene transcription, because MCP-1 mRNA levels in oligonucleotide-treated cells 
      were also decreased by approximately 40%.
FAU - Marchand, P
AU  - Marchand P
AD  - Institute of Pharmacology, Medical School Hannover, Hannover, Germany.
FAU - Resch, K
AU  - Resch K
FAU - Radeke, H H
AU  - Radeke HH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Chemokine CCL2)
RN  - 0 (Oligonucleotides)
RN  - 0 (Sp1 Transcription Factor)
SB  - IM
MH  - Binding, Competitive/genetics/immunology
MH  - Cell Line
MH  - Chemokine CCL2/*antagonists & inhibitors/biosynthesis/*genetics/metabolism
MH  - *Gene Expression Regulation/drug effects
MH  - Gene Targeting
MH  - Genetic Vectors/immunology/metabolism
MH  - Humans
MH  - Kidney/*cytology/embryology/*metabolism
MH  - Nucleic Acid Conformation
MH  - Oligonucleotides/chemical synthesis/metabolism/*pharmacology
MH  - Promoter Regions, Genetic/drug effects/immunology
MH  - Sp1 Transcription Factor/antagonists & inhibitors/metabolism
EDAT- 2000/02/05 09:00
MHDA- 2000/03/11 09:00
CRDT- 2000/02/05 09:00
PHST- 2000/02/05 09:00 [pubmed]
PHST- 2000/03/11 09:00 [medline]
PHST- 2000/02/05 09:00 [entrez]
AID - ji_v164n4p2070 [pii]
AID - 10.4049/jimmunol.164.4.2070 [doi]
PST - ppublish
SO  - J Immunol. 2000 Feb 15;164(4):2070-6. doi: 10.4049/jimmunol.164.4.2070.