Suppression of NF kappa B activation and NF kappa B-dependent gene expression by tepoxalin, a dual inhibitor of cyclooxygenase and 5-lipoxygenase.
Tepoxalin, a dual inhibitor of cyclooxygenase (CO) and 5-lipoxygenase (5LO) with cytokine modifying activity, is also a potent inhibitor of the transcription factor, nuclear factor kappa B (NF kappa B). NF kappa B is a pleiotropic activator that is involved in the regulation of many genes whose products participate in immune or inflammatory responses. Tepoxalin inhibited in a dose related manner NF kappa B activation by PMA + ionomycin or H2O2 in Jurkat and HeLa cells. TNF-alpha-induced NF kappa B was also inhibited by tepoxalin in HeLa cells, while relatively less marked inhibition was observed in Jurkat cells. Activation of NF kappa B in several monocytic cell lines was also suppressed by tepoxalin. However AP-1 stimulation under the same conditions was not affected by tepoxalin. Other CO, LO inhibitors such as naproxen or zileuton did not inhibit NF kappa B activities. This inhibitory activity of tepoxalin was further illustrated by its suppression of NF kappa B regulated genes such as IL-6 in PMA stimulated human PBL and c-myc in IL-2 dependent T cell lines. Tepoxalin also blocked PMA + ionomycin-induced I kappa B degradation in a time-dependent fashion. The possible mechanism of tepoxalin in NF kappa B activation and its potential clinical application are discussed.
Kazmi
S M
SM
R.W. Johnson Pharmaceutical Research Institute, Don Mills, Ontario, Canada.
Plante
R K
RK
Visconti
V
V
Taylor
G R
GR
Zhou
L
L
Lau
C Y
CY
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D017931:DNA Primers; D015870:Gene Expression / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis*; D015759:Ionomycin / Q000494:pharmacology; D007700:Kinetics; D016859:Lipoxygenase Inhibitors; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009288:Naproxen / Q000494:pharmacology; D009838:Oligodeoxyribonucleotides; D016133:Polymerase Chain Reaction; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D011720:Pyrazoles / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000096:biosynthesis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D017931:DNA Primers; D015850:Interleukin-6; D016859:Lipoxygenase Inhibitors; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D016271:Proto-Oncogene Proteins c-myc; D011720:Pyrazoles; D011994:Recombinant Proteins; D015759:Ionomycin; D009288:Naproxen; D015500:Chloramphenicol O-Acetyltransferase; D013755:Tetradecanoylphorbol Acetate; C073135:tepoxalin; C063449:zileuton; D006918:Hydroxyurea