CYCLOSPORINE-A INHIBITS THE INTERLEUKIN-2 RECEPTOR ALPHA-CHAIN GENE-TRANSCRIPTION BUT NOT ITS CELL-SURFACE EXPRESSION - THE ALPHA-CHAIN STABILITY CAN EXPLAIN THIS DISCREPANCY

The effect of the immunosuppressor cyclosporin A (CsA) on the expression of interleukin (IL) 2 receptors was investigated in a human T cell line IARC301 which constitutively expresses such receptors. This cell line also spontaneously secretes IL 2 which supports its autocrine growth. We have previously shown that CsA prevents the constitutive transcription of the IL 2 gene in these cells. Here we show that as soon as 4 h after CsA addition, the transcription of the gene encoding the alpha chain (p55) of IL 2R was inhibited. IL 2 can transiently increase the expression of this gene. CsA did not prevent this transient IL 2-dependent induction of IL 2R-alpha, but could still partially inhibit it. Once IL 2 induction was over, CsA exerted its full inhibition. Thus, CsA does not seem to inhibit IL 2R-alpha gene transcription simply by inhibition of IL 2 synthesis. However, no modification of IL 2R-alpha expression on the cell surface could be detected after 48 h in the presence of CsA. This discrepancy between the effect of CsA on IL 2R-alpha expression as probed at the mRNA or the protein level can be accounted for by the stability of the IL 2R-alpha protein after synthesis. Indeed, the half-life of IL 2R-alpha chain is longer than 40 h. This suggests that the alpha chain, after it is endocytosed together with the beta chain as a component of high-affinity IL 2R, might recycle back to the cell surface.