Immunosuppressant PG490 (triptolide) inhibits T-cell interleukin-2 expression at the level of purine-box/nuclear factor of activated T-cells and NF-kappaB transcriptional activation.
PG490 (triptolide) is a diterpene triepoxide with potent immunosuppressive and antiinflammatory properties. PG490 inhibits interleukin(IL)-2 expression by normal human peripheral blood lymphocytes stimulated with phorbol 12-myristate 13-acetate (PMA) and antibody to CD3 (IC50 of 10 ng/ml), and with PMA and ionomycin (Iono, IC50 of 40 ng/ml). In Jurkat T-cells, PG490 inhibits PMA/Iono-stimulated IL-2 transcription. PG490 inhibits the induction of DNA binding activity at the purine-box/antigen receptor response element (ARRE)/nuclear factor of activated T-cells (NF-AT) target sequence but not at the NF-kappaB site. PG490 can completely inhibit transcriptional activation at the purine-box/ARRE/NF-AT and NF-kappaB target DNA sequences triggered by all stimuli examined (PMA, PMA/Iono, tumor necrosis factor-alpha). PG490 also inhibits PMA-stimulated activation of a chimeric transcription factor in which the C-terminal TA1 transactivation domain of NF-kappaB p65 is fused to the DNA binding domain of GAL4. In 16HBE human bronchial epithelial cells, IL-8 expression is regulated predominantly by NF-kappaB, and PG490 but not cyclosporin A can completely inhibit expression of IL-8. The mechanism of PG490 inhibition of cytokine gene expression differs from cyclosporin A and involves nuclear inhibition of transcriptional activation of NF-kappaB and the purine-box regulator operating at the ARRE/NF-AT site at a step after specific DNA binding.
Qiu
D
D
Pulmonary and Critical Care Medicine, Stanford University Medical Center, Stanford, California 94305-5236, USA.
Zhao
G
G
Aoki
Y
Y
Shi
L
L
Uyei
A
A
Nazarian
S
S
Ng
J C
JC
Kao
P N
PN
D001665:Binding Sites; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004224:Diterpenes / Q000494:pharmacology*; D004742:Enhancer Elements, Genetic; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D004852:Epoxy Compounds; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism*; D010616:Phenanthrenes; D011687:Purines / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015533:Transcriptional Activation
D004224:Diterpenes; D004852:Epoxy Compounds; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D016209:Interleukin-8; D016328:NF-kappa B; D010616:Phenanthrenes; D011687:Purines; C001899:triptolide; D016572:Cyclosporine; D013755:Tetradecanoylphorbol Acetate