Journal
BIOCHEMICAL PHARMACOLOGY
Volume 80, Issue 9, Pages 1365-1372Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2010.07.032
Keywords
Dimethylcelecoxib; mPGES-1; COX-inhibitor; EGR1; NF-kappa B
Categories
Funding
- European Graduate School [DFG GRK 757/1]
- DFG [Ge 695]
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DMC (dimethylcelecoxib = {4-[5-(2,5-dimethylphenyl)-3(trifluoromethyl)-1H-pyrazol-1-yl]benzene-sulfonamide}) is a close derivative of celecoxib, without cyclooxygenase inhibiting properties up to very high concentrations. Nevertheless, after stimulation of various human cell lines with IL-1 beta/TNF alpha and simultaneous treatment with DMC PGE(2) synthesis is inhibited [1]. Here we investigated the effect of DMC on mPGES-1 promoter activity, using a reporter gene assay. Our data demonstrate that DMC inhibits mPGES-1 promoter activity by blocking nuclear EGR1 expression and repressing NF-kappa B transcriptional activity. Other putative transcription factors, known to regulate mPGES-1 expression, such as SP1 or CREB are not affected by DMC. Over-expression of EGR1 completely prevents the inhibitory effect of DMC on mPGES-1 promoter activity, indicating that the repressing effect of DMC on mPGES-1 expression is mainly dependent on blocking EGR1 expression. mPGES-1, EGR1 and NF-kappa B are important proteins involved in many pathological conditions such as inflammation and cancer. Therefore, DMC seems to be a promising substance to treat inflammatory and carcinogenic processes, although it does not inhibit cyclooxygenases. (C) 2010 Elsevier Inc. All rights reserved.
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