Dimethylcelecoxib inhibits mPGES-1 promoter activity by influencing EGR1 and NF-κB.
DMC (dimethylcelecoxib={4-[5-(2,5-dimethylphenyl)-3(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide}) 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-1β/TNFα 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-κB 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-κB 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.
Deckmann
Klaus
K
Pharmazentrum Frankfurt/ZAFES, Institute for Clinical Pharmacology, Johann Wolfgang Goethe-University Frankfurt, Frankfurt/Main, Germany.
Rörsch
Florian
F
Steri
Ramona
R
Schubert-Zsilavecz
Manfred
M
Geisslinger
Gerd
G
Grösch
Sabine
S
D001665:Binding Sites; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D051766:Early Growth Response Protein 1 / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000235:genetics*; D016328:NF-kappa B / Q000502:physiology*; D011401:Promoter Regions, Genetic; D000071876:Prostaglandin-E Synthases; D011720:Pyrazoles / Q000494:pharmacology*; D016329:Sp1 Transcription Factor / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C506698:2,5-dimethylcelecoxib; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D053583:Interleukin-1beta; D016328:NF-kappa B; D011720:Pyrazoles; D016329:Sp1 Transcription Factor; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases