Cytokine-modulating activity of tepoxalin, a new potential antirheumatic.
Tepoxalin is a new dual cyclooxygenase/5-lipoxygenase anti-inflammatory compound currently under clinical investigation. It has been shown to possess anti-inflammatory activity in a variety of animal models and more recently to inhibit IL-2 induced signal transduction. The current study was conducted to evaluate the cytokine modulating activity of tepoxalin and the role of iron in these effects. In human peripheral blood mononuclear cells (PBMC) stimulated with OKT3/PMA, tepoxalin inhibited lymphocyte proliferation with an IC50 of 6 microM. Additionally, it inhibited the production of LTB4 (IC50 = 0.5 microM) and the cytokines IL-2, IL-6 and TNF alpha (IC50 = 10-12 microM). Cytotoxicity was not demonstrated at these concentrations. Add-back experiments with either cytokines (IL-2 or IL-6), LTB4 or conditioned media failed to restore the proliferative response in the presence of tepoxalin. However, the concurrent addition of iron (in the form of ferrous or ferric chloride and other iron salts) reversed the inhibition of proliferation caused by tepoxalin. Tepoxalin also inhibits the activation of NF kappa B, a transcription factor which acts on several cytokine genes. Tepoxalin's effect on NF kappa B is also reversed by the addition of iron salts. These data suggest that the action of tepoxalin to inhibit proliferation in PBMC may be at least in part due to its ability to reduce the amount of available iron resulting in decreased activation of NF kappa B and subsequent inhibition of cytokine production.
Ritchie
D M
DM
R. W. Johnson Pharmaceutical Research Institute, Raritan, NJ 08869, USA.
Argentieri
D C
DC
Aparicio
B L
BL
Plante
R K
RK
Lau
C Y
CY
Barbone
A G
AG
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D018501:Antirheumatic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors*; D005296:Ferrous Compounds / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors*; D016328:NF-kappa B / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018501:Antirheumatic Agents; D016207:Cytokines; D005296:Ferrous Compounds; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D011720:Pyrazoles; D007975:Leukotriene B4; C073135:tepoxalin