Selective suppression of CCAAT/enhancer-binding protein beta finding and cyclooxygenase-2 promoter activity by sodium salicylate in quiescent human fibroblasts

The anti-inflammatory actions of salicylates cannot be explained by inhibit ion of cyclooxygenase (COX) activity. This study demonstrates that sodium s alicylate at a therapeutic concentration suppressed COX-2 gene transcriptio n induced by phorbol 12-myristate 13-acetate and interleukin 1 beta by inhi biting the binding of CCAAT/ enhancer-binding protein beta to its promoter region of COX-2. By contrast, salicylate did not inhibit nuclear factor kap pa beta -dependent COX-2 induction by tumor necrosis factor alpha. The inhi bitory effect of sodium salicylate was restricted to serum-deprived quiesce nt cells. These findings indicate that contrary to the current view that sa licylate acts via inhibition of nuclear factor kappa beta the pharmacologic al actions of aspirin and salicylates are mediated by inhibiting CCAAT/enha ncer-binding protein beta binding and transactivation. These findings have a major impact on the conceptual understanding of the mechanism of action o f salicylates and on new drug discovery and design.