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.