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 considere d to be a result of their inhibitory effect on cyclooxygenase (COX) activit y. 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 nec rosis factor alpha (TNF alpha)- or lipopolysaccharide (LPS)-induced COX-2 e xpression. This inhibition correlates with the suppression of TNF alpha- or LPS-induced NF kappa B activation by flufenamic acid. The inhibitor of ext racellular signal-regulated protein kinase, p38, or NF kappa B does not aff ect the NSAID-induced COX-2 expression. These results suggest that the NSAI D-induced COX-2 expression is not mediated through activation of NF kappa B and mitogen-activated protein kinases, An activator of peroxisome prolifer ator activated receptor gamma, 15-deoxy-Delta(12,14)-prostaglandin J(2), al so induces COX-2 expression and inhibits TNF alpha-induced NF kappa B activ ation and COX-2 expression, Flufenamic acid and 15-deoxy-Delta(12,14)-prost aglandin J(2) also inhibit LPS-induced expression of inducible form of nitr ic-oxide synthase and interleukin-1 alpha in RAW 264.7 cells. Together, the se results indicate that the NSAIDs inhibit mitogen-induced COX-2 expressio n 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 effe ct on COX enzyme activity.