Cyclosporin A inhibits induction of IL-2 receptor alpha chain expression by affecting activation of NF-kB-like factor(s) in cultured human T lymphocytes.
We have examined the effect and potential mechanism of Cyclosporin A (CsA) on the Interleukin-2-receptor alpha chain (IL-2R alpha) expression in human T-lymphocytes. CsA pretreatment of PHA-activated T-cells led to 30-50% decrease in Tac antigen surface expression and a concomitant decrease in the steady state IL-2R alpha mRNA levels. Transacting factors which recognize a kB-like sequence present in the IL-2R alpha chain regulatory region have been suggested to participate in the transcriptional regulation of the IL-2R alpha gene. Using oligonucleotides corresponding to the 5' regulatory region of the IL-2R alpha gene (i.e. 245 to 291 bp upstream of the start codon) and nuclear extract from resting T lymphocytes, we detected two specific bands by gel mobility shift assay. One of these bands is specifically increased after stimulation with phytohemagglutinin (PHA) and it is inhibited by CsA pretreatment. The same pattern of binding activity has been observed with the tandem repeat of NF-kB binding site present in the enhancer element of the human immunodeficiency virus long terminal repeat (HIV-1 LTR). These data suggest that CsA affects IL-2R receptor alpha chain expression by inhibiting the interaction of transacting factors to kB-like sequences after PHA activation. These findings may be of some relevance for the understanding of the immunosuppressive effects of CsA in normal human T lymphocytes.
Brini
A T
AT
Laboratory of Molecular Immunoregulation, National Cancer Institute, Frederick, MD 21701-1013.
Harel-Bellan
A
A
Farrar
W L
WL
D001483:Base Sequence; D015152:Blotting, Northern; D016572:Cyclosporine / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D010835:Phytohemagglutinins / Q000494:pharmacology; D011485:Protein Binding; D012333:RNA, Messenger / Q000032:analysis; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects*
D016328:NF-kappa B; D010835:Phytohemagglutinins; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D016572:Cyclosporine; D004247:DNA