CYTOKINE-MODULATING ACTIVITY OF TEPOXALIN, A NEW POTENTIAL ANTIRHEUMATIC

Tepoxalin is a new dual cyclooxygenase/5-lipoxygenase anti-inflammator y compound currently under clinical investigation. It has been shown t o possess anti-inflammatory activity in a variety of animal models and more recently to inhibit IL-2 induced signal transduction. The curren t study was conducted to evaluate the cytokine modulating activity of tepoxalin and the role of iron in these effects. In human peripheral b lood mononuclear cells (PBMC) stimulated with OKT3/PMA, tepoxalin inhi bited lymphocyte proliferation with an IC50 of 6 mu M. Additionally, i t inhibited the production of LTB(4) (IC50 = 0.5 mu M) and the cytokin es IL-2, IL-6 and TNF alpha (IC50 = 10-12 mu M). Cytotoxicity was not demonstrated at these concentrations. Add-back experiments with either cytokines (IL,-2 or IL-6), LTB(4) or conditioned media failed to rest ore the proliferative response in the presence of tepoxalin. However, the concurrent addition of iron (in the form of ferrous or ferric chlo ride and other iron salts) reversed the inhibition of proliferation ca used by tepoxalin. Tepoxalin also inhibits the activation of NF kappa B, a transcription factor which acts on several cytokine genes. Tepoxa lin's effect on NF kappa B is also reversed by the addition of iron sa lts. These data suggest that the action of tepoxalin to inhibit prolif eration in PBMC may be at least in part due to its ability to reduce t he amount of available iron resulting in decreased activation of NF ka ppa B and subsequent inhibition of cytokine production.