Celecoxib potently inhibits TNFα-induced nuclear translocation and activation of NF-κB

Celecoxib is a specific inhibitor of cyclooxygenase 2 (COX2). While it has been used for the treatment of chronic inflammatory conditions, including rheumatoid arthritis, its detailed anti-inflammatory mechanism has not been clarified. Here, we found that Celecoxib potently inhibited TNF alpha-induced transcriptional activity and DNA binding activity of NF-kappa B; however, Celecoxib had no effect on TNF alpha-induced IKK activation and degradation of I kappa B alpha and I kappa B beta, suggesting that it inhibited NF-kappa B activation via suppressing downstream of IKK activation and I kappa Bs degradation. Interestingly, it was also found that Celecoxib abrogated TNF alpha-induced nuclear accumulation of the NF-kappa B p65 subunit. As a result, TNF alpha-induced expression of inflammatory cytokines, CXCL1/KC and CCL2/MCP-1, was clearly inhibited by Celecoxib. On the other hand, Celecoxib had no effect on the TNF alpha-induced nuclear translocation of c-jun and activation of ERK, JNK, p38 and Akt. Taken together, these data indicate that Celecoxib specifically inhibits TNF alpha-induced NF-kappa B activation at the level of its nuclear translocation. This negative regulation of NF-kappa B activation by Celecoxib might be an important mechanism leading to its anti-inflammatory activity. (C) 2008 Elsevier Inc. All rights reserved.