Two opposing effects of non-steroidal anti-inflammatory drugs on the expression of the inducible cyclooxygenase: Mediation through different signaling pathways

The efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) is considered to be a result of their inhibitory effect on cyclooxygenase (COX) activity. Here, we report that flufenamic acid shows two opposing effects on COX-2 expression; it induces COX-2 expression in the colon cancer cell line (HT-29) and macrophage cell line (RAW 264.7); conversely, it inhibits tumor necrosis factor α (TNFα)- or lipopolysaccharide (LPS)-induced COX-2 expression. This inhibition correlates with the suppression of TNFα- or LPS-induced NFκB activation by flufenamic acid. The inhibitor of extracellular signal-regulated protein kinase, p38, or NFκB does not affect the NSAID-induced COX-2 expression. These results suggest that the NSAID-induced COX-2 expression is not mediated through activation of NFκB and mitogen-activated protein kinases. An activator of peroxisome proliferator-activated receptor γ, 15-deoxy-Δ^12,14-prostaglandin J₂, also induces COX-2 expression and inhibits TNFα-induced NFκB activation and COX-2 expression. Flufenamic acid and 15-deoxy-Δ^12,14-prostaglandin J₂ also inhibit LPS-induced expression of inducible form of nitric-oxide synthase and interleukin-1α in RAW 264.7 cells. Together, these results indicate that the NSAIDs inhibit mitogen-induced COX-2 expression while they induce COX-2 expression. Furthermore, the results suggest that the anti-inflammatory effects of flufenamic acid and some other NSAIDs are due to their inhibitory action on the mitogen-induced expression of COX-2 and downstream markers of inflammation in addition to their inhibitory effect on COX enzyme activity.