IL-7 DIFFERENTIALLY MODULATES THE EXPRESSION OF IFN-GAMMA AND IL-4 INACTIVATED HUMAN T-LYMPHOCYTES BY TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL MECHANISMS

We investigated the role of IL-7 on the expression of IFN-gamma and IL -4 in human T lymphocytes, IL-7 alone did not induce IFN-gamma or IL-4 mRNA, However, IL-7 dose-dependently up-regulates the anti-CD3- or an ti-CD3/anti-CD28-induced IFN-gamma and IL-4 mRNA expression. Used at a n optimal concentration, IL-7 (5 ng/ml) increased the accumulation of IFN-gamma (eightfold) and IL-4 (2.5-fold) mRNAs, which could not be bl ocked by anti-IL-12 treatment. The enhanced IFN-gamma mRNA accumulatio n was observed within 3 to 6 h, without altering the pattern of the ki netics, However, longer exposure (>12 h) did not result in different I FN-gamma expression for anti-CD3/anti-CD28 vs anti-CD3/anti-CD28 plus IL-7-stimulated T lymphocytes. mRNA stability studies revealed that IL -7 stabilizes both IFN-gamma and IL-4 mRNA transcripts: 40 and 60 min in anti-CD3/anti-CD28-stimulated T cells vs 120 and 90 min in T cells costimulated with anti-CD3/anti-CD28 plus IL-7. Nuclear run-on assays revealed that the transcription rate of the IFN-gamma gene increased a pproximately twofold in the presence of IL-7, without affecting the tr anscription rate of the IL-4 gene, The IL-7-mediated IFN-gamma up-regu lation could not be inhibited by cycloheximide treatment, in contrast to IL-4 gene expression. However, the promotive effect of IL-7 on IFN- gamma and IL-4 gene expression could be blocked by genistein and cyclo sporin A. Finally, it was demonstrated that the effect of IL-7 on IFN- gamma mRNA accumulation was also reflected at the protein level, In su mmary, these data demonstrate that IL-7 preferentially up-regulates IF N-gamma expression in activated T lymphocytes, which is accomplished a t transcriptional and post-transcriptional levels.