Regulation of T cell activation by cytochrome P450 inhibitors.
Cytochrome P450 inhibitors such as alpha-naphthoflavone, the imidazole antimycotics, econazole, clotrimazole, and miconazole and the lipoxygenase inhibitors, nordihydroguaiaretic acid and eicosatetraynoic acid, strongly diminished CD3-induced human T cell proliferation. This effect is due to a marked inhibition of IL-2 synthesis. The mechanism leading to the in vitro immunosuppressive effect of cytochrome P450 inhibitors appears to be a consequence of a blockade of Ca2+ influx induced by CD3 mAb. The drugs tested did not interfere with the release of Ca2+ from the endoplasmic reticulum as demonstrated by Ca+ measurements in the presence of the Ca2+ chelator, EGTA. Measurements of CD3-induced changes in phosphatidylserine synthesis, which reflect the status (full/empty) of intracellular Ca2+ stores confirmed that CD3 mAb remained able to empty the Ca2+ stores either alone or in the presence of cytochrome P450 inhibitors. Altogether, our results support the hypothesis that a cytochrome P450 regulates Ca2+ influx in T cells and are consistent with the proposal that impairing Ca2+ influx leads to the inhibition of IL-2 synthesis and subsequent T cell proliferation.
Aussel
C
C
Interactions Cellulaires et Moléculaires en Immunologie, INSERM U343, Nice, France.
Breittmayer
J P
JP
Ticchioni
M
M
Pelassy
C
C
Bernard
A
A
D001692:Biological Transport; D017252:CD3 Complex / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D009637:Masoprocol / Q000494:pharmacology; D010718:Phosphatidylserines / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000187:drug effects*
D017252:CD3 Complex; D065607:Cytochrome P-450 Enzyme Inhibitors; D007376:Interleukin-2; D016859:Lipoxygenase Inhibitors; D010718:Phosphatidylserines; D009637:Masoprocol; D002118:Calcium