IL-7 differentially modulates the expression of IFN-gamma and IL-4 in activated human T lymphocytes by transcriptional and post-transcriptional 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 anti-CD3/anti-CD28-induced IFN-gamma and IL-4 mRNA expression. Used at an 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 blocked by anti-IL-12 treatment. The enhanced IFN-gamma mRNA accumulation was observed within 3 to 6 h, without altering the pattern of the kinetics. However, longer exposure (> 12 h) did not result in different IFN-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 approximately twofold in the presence of IL-7, without affecting the transcription rate of the IL-4 gene. The IL-7-mediated IFN-gamma up-regulation 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 cyclosporin A. Finally, it was demonstrated that the effect of IL-7 on IFN-gamma mRNA accumulation was also reflected at the protein level. In summary, these data demonstrate that IL-7 preferentially up-regulates IFN-gamma expression in activated T lymphocytes, which is accomplished at transcriptional and post-transcriptional levels.
Borger
P
P
Department of Medicine, University of Groningen, The Netherlands.
Kauffman
H F
HF
Postma
D S
DS
Vellenga
E
E
D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D019833:Genistein; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics* / Q000378:metabolism; D015851:Interleukin-7 / Q000502:physiology*; D007529:Isoflavones / Q000494:pharmacology; D008213:Lymphocyte Activation; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation
D004791:Enzyme Inhibitors; D015851:Interleukin-7; D007529:Isoflavones; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D015847:Interleukin-4; D007371:Interferon-gamma; D016572:Cyclosporine; D003513:Cycloheximide; D019833:Genistein; D011505:Protein-Tyrosine Kinases