the time, it was not known that human vascular endothelial cells express the inducible COX-2 isoform after stimulation by cytokines. Later work suggested that salicylate, after entering the cell, interacts with the CCAT/enhancer-binding protein-b (C/EBP-b) in the nucleus, prevents the binding of this transcription factor, and downregulates COX-2 gene expression. This effect is seen at therapeutic analgesic/anti-inflammatory concentrations (0.01-<1mM) of the compounds. At higher concentrations (>1 mM) salicylates additionally inhibit the binding of additional transcription factors, such as nuclear factor kB (NFkB) . These effects of salicylates are not limited to COX-2 but are also seen with inducible NO synthase (iNOS) and probably many other genes that are regulated by the same transcription factors in their promoter region. This issue is discussed in more detail in Section 2.2.2. Similar to salicylates, naproxen was also found to transcriptionally downregulate COX-2 (and COX-1) protein expression . Whether this also applies to other traditional NSAIDs is unknown.
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