TEPOXALIN, A NOVEL IMMUNOSUPPRESSIVE AGENT WITH A DIFFERENT MECHANISMOF ACTION FROM CYCLOSPORINE-A

Tepoxalin, a compound previously identified as a dual cyclooxygenase/l ipoxygenase (CO/LO) inhibitor, is a potent inhibitor of T cell prolife ration. Comparing the suppressive effects of tepoxalin and cyclosporin A (CsA) on OKT3-, PMA-, IL-2-, and PMA + ionomycin-induced T cell pro liferations revealed marked differences in the mechanism of action bet ween the two compounds. Whereas CsA was most effective in suppressing OKT3-stimulated proliferation, tepoxalin was more potent in inhibiting PMA-, PMA + ionomycin-, and IL-2-induced proliferation. Quantitative PCR (QPCR) assays used to detect cytokine messages showed that tepoxal in blocked IL-2 mRNA transcription in PMA- and PMA + ionomycin-, but n ot OKT3-stimulated T cells whereas CsA was most potent in inhibiting O KT3-induced IL-2 mRNA induction in these cells. Both tepoxalin and CsA did not inhibit the expression of IL-2R; however, only tepoxalin, but not CsA, inhibited the proliferation of IL-2-dependent blasts and the transcription of IFN-gamma, an IL-2-dependent target gene. Moreover, addition of exogenous IL-2 restored OKT3-induced proliferation to CsA- but not tepoxalin-treated cells. These data suggest that tepoxalin, b ut not CsA, suppressed T cell proliferation by inhibiting IL-2-induced signal transduction. Consistent with these findings, tepoxalin, unlik e CsA, which was most potent when added at the initiation of OKT3 stim ulation, was equally active, regardless of whether it was added at the beginning or 48 h after culture initiation. The difference in mechani sm of action between tepoxalin and CsA was confirmed further by the sy nergistic suppressive effects on T cell proliferation upon co-administ ration of the two compounds.