J Immunol 2004,
PMID: 15265936
Shishodia, Shishir; Koul, Dimpy; Aggarwal, Bharat B
The cyclooxygenase 2 (COX-2) inhibitor celecoxib (also called celebrex), approved for the treatment of colon carcinogenesis, rheumatoid arthritis, and other inflammatory diseases, has been shown to induce apoptosis and inhibit angiogenesis. Because NF-kappa B plays a major role in regulation of apoptosis, angiogenesis, carcinogenesis, and inflammation, we postulated that celecoxib modulates NF-kappa B. In the present study, we investigated the effect of this drug on the activation of NF-kappa B by a wide variety of agents. We found that celecoxib suppressed NF-kappa B activation induced by various carcinogens, including TNF, phorbol ester, okadaic acid, LPS, and IL-1 beta. Celecoxib inhibited TNF-induced I kappa B alpha kinase activation, leading to suppression of I kappa B alpha phosphorylation and degradation. Celecoxib suppressed both inducible and constitutive NF-kappa B without cell type specificity. Celecoxib also suppressed p65 phosphorylation and nuclear translocation. Akt activation, which is required for TNF-induced NF-kappa B activation, was also suppressed by this drug. Celecoxib also inhibited the TNF-induced interaction of Akt with I kappa B alpha kinase (IKK). Celecoxib abrogated the NF-kappa B-dependent reporter gene expression activated by TNF, TNF receptor, TNF receptor-associated death domain, TNF receptor-associated factor 2, NF-kappa B-inducing kinase, and IKK, but not that activated by p65. The COX-2 promoter, which is regulated by NF-kappa B, was also inhibited by celecoxib, and this inhibition correlated with suppression of TNF-induced COX-2 expression. Besides NF-kappa B, celecoxib also suppressed TNF-induced JNK, p38 MAPK, and ERK activation. Thus, overall, our results indicate that celecoxib inhibits NF-kappa B activation through inhibition of IKK and Akt activation, leading to down-regulation of synthesis of COX-2 and other genes needed for inflammation, proliferation, and carcinogenesis.
Diseases/Pathways annotated by Medline MESH: Carcinoma, Non-Small-Cell Lung, Lung Neoplasms, MAP Kinase Signaling System
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Text Mining Data
NF-kappa B → TNF: "
Cyclooxygenase (COX)-2 inhibitor celecoxib abrogates
TNF induced
NF-kappa B activation through inhibition of activation of I kappa B alpha kinase and Akt in human non-small cell lung carcinoma : correlation with suppression of COX-2 synthesis
"
alpha kinase → TNF: "
Celecoxib inhibited TNF induced I kappa B alpha kinase activation, leading to suppression of I kappa B alpha phosphorylation and degradation
"
I kappa B alpha → TNF: "
Celecoxib inhibited TNF induced I kappa B alpha kinase activation , leading to suppression of I kappa B alpha phosphorylation and degradation
"
NF-kappa B → TNF: "
Akt activation, which is required for TNF induced NF-kappa B activation, was also suppressed by this drug
"
Akt → TNF: "
Celecoxib also inhibited the TNF induced interaction of Akt with I kappa B alpha kinase (IKK)
"
COX-2 → TNF: "
The COX-2 promoter, which is regulated by NF-kappa B, was also inhibited by celecoxib, and this inhibition correlated with suppression of TNF induced COX-2 expression
"
Manually curated Databases
No curated data.