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Celecoxib loses its anti‐inflammatory efficacy at high doses through activation of NF‐κB
Author(s) -
Niederberger Ellen,
Tegeder Irmgard,
Vetter Gregor,
Schmidtko Achim,
Schmidt Helmut,
Euchenhofer Christian,
Bräutigam Lutz,
Grösch Sabine,
Geisslinger Gerd
Publication year - 2001
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.00-0716fje
Subject(s) - celecoxib , nf κb , pharmacology , medicine , anti inflammatory , nfkb1 , inflammation , chemistry , biochemistry , transcription factor , gene
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 ≥100 mg/kg. To evaluate the underlying mechanisms, we used rat renal mesangial cells as a cell culture model. In these cells, celecoxib (50 μM) increased the interleukin Iβ stimulated nuclear translocation and DNA binding of NF‐κB and facilitated the degradation of I‐κB. Consequently, COX‐2 and tumor necrosis factor α (TNF‐α) expression were increased. The up‐regulation of COX‐2 and TNF‐α also occurred in the spinal cord of rats treated with celecoxib (≥100 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‐α and possibly other NF‐κB regulated proinflammatory genes might worsen the pathophysiological processes underlying chronic arthritis.