Tepoxalin, a novel immunosuppressive agent with a different mechanism of action from cyclosporin A.
Tepoxalin, a compound previously identified as a dual cyclooxygenase/lipoxygenase (CO/LO) inhibitor, is a potent inhibitor of T cell proliferation. Comparing the suppressive effects of tepoxalin and cyclosporin A (CsA) on OKT3-, PMA-, IL-2-, and PMA+ionomycin-induced T cell proliferations revealed marked differences in the mechanism of action between 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 tepoxalin blocked IL-2 mRNA transcription in PMA- and PMA+ionomycin-, but not OKT3-stimulated T cells whereas CsA was most potent in inhibiting OKT3-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, but not CsA, suppressed T cell proliferation by inhibiting IL-2-induced signal transduction. Consistent with these findings, tepoxalin, unlike CsA, which was most potent when added at the initiation of OKT3 stimulation, was equally active, regardless of whether it was added at the beginning or 48 h after culture initiation. The difference in mechanism of action between tepoxalin and CsA was confirmed further by the synergistic suppressive effects on T cell proliferation upon co-administration of the two compounds.
R. W. Johnson Pharmaceutical Research Institute, Ontario, Canada.
L
L
Zhou
D
D
Ritchie
E Y
EY
Wang
A G
AG
Barbone
D
D
Argentieri
C Y
CY
Lau
D001483:Base Sequence; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015759:Ionomycin / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008969:Molecular Sequence Data; D016853:Muromonab-CD3; D016133:Polymerase Chain Reaction; D011720:Pyrazoles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D016853:Muromonab-CD3; D011720:Pyrazoles; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D015759:Ionomycin; D016572:Cyclosporine; D013755:Tetradecanoylphorbol Acetate; C073135:tepoxalin