Celecoxib potently inhibits TNFalpha-induced nuclear translocation and activation of NF-kappaB.
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 TNFalpha-induced transcriptional activity and DNA binding activity of NF-kappaB; however, Celecoxib had no effect on TNFalpha-induced IKK activation and degradation of IkappaBalpha and IkappaBbeta, suggesting that it inhibited NF-kappaB activation via suppressing downstream of IKK activation and IkappaBs degradation. Interestingly, it was also found that Celecoxib abrogated TNFalpha-induced nuclear accumulation of the NF-kappaB p65 subunit. As a result, TNFalpha-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 TNFalpha-induced nuclear translocation of c-jun and activation of ERK, JNK, p38 and Akt. Taken together, these data indicate that Celecoxib specifically inhibits TNFalpha-induced NF-kappaB activation at the level of its nuclear translocation. This negative regulation of NF-kappaB activation by Celecoxib might be an important mechanism leading to its anti-inflammatory activity.
Funakoshi-Tago
Megumi
M
Department of Biochemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan. tago-mg@pha.keio.ac.jp
Shimizu
Taeko
T
Tago
Kenji
K
Nakamura
Motohiro
M
Itoh
Hiroshi
H
Sonoda
Yoshiko
Y
Kasahara
Tadashi
T
D000818:Animals; D000068579:Celecoxib; D002467:Cell Nucleus / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D041681:NIH 3T3 Cells; D016133:Polymerase Chain Reaction; D021381:Protein Transport / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
D052246:Cyclooxygenase 2 Inhibitors; D016328:NF-kappa B; D011720:Pyrazoles; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D000068579:Celecoxib