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Institute of Pharmacology, Medical School Hannover, Hannover, Germany
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-1ß, TNF-
, and IFN-
. 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 
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--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 µM 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
40%.
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