Celecoxib loses its anti-inflammatory efficacy at high doses through activation of NF-κB

Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, has recently been approved for the symptomatic treatment of arthritis. In some clinical studies, doses of 400 and 800 mg/day provided somewhat less efficacy compared with 200 mg/day, which suggests an early ceiling effect. Using the zymosan-induced inflammation model in rats, we show that celecoxib significantly reduces paw swelling at 50 mg/kg but completely loses its anti-inflammatory efficacy at doses greater than or equal to100 mg/kg. To evaluate the underlying mechanisms, we used rat renal mesangial cells as a cell culture model. In these cells, celecoxib (50 muM) increased the interleukin Ibeta stimulated nuclear translocation and DNA binding of NF-kappaB and facilitated the degradation of I-kappaB. Consequently, COX-2 and tumor necrosis factor alpha (TNF-alpha) expression were increased. The up-regulation of COX-2 and TNF-alpha also occurred in the spinal cord of rats treated with celecoxib (greater than or equal to100 mg/kg), indicating that in vitro mechanisms were relevant in vivo. Clinically, the overexpression. of COX-2 might be less important because celecoxib inhibits COX-2 enzymatically. However, the up-regulation of TNF-alpha and possibly other NF-kappaB regulated proinflammatory genes might worsen the pathophysiological processes underlying chronic arthritis.