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Pulmonary and Critical Care Medicine, Stanford University Medical Center, Stanford, California 94305-5236
Triptolide (PG490, 97% pure) is a diterpenoid
triepoxide with potent anti-inflammatory and immunosuppressive effects
in transformed human bronchial epithelial cells and T cells (Qiu D,
Zhao G, Aoki Y, Shi L, Uyei A, Nazarian S, Ng JC-H, and Kao PN.
J Biol Chem 274: 13443-13450, 1999). Triptolide,
with an IC50 of ~20-50 ng/ml, inhibits normal and
transformed human bronchial epithelial cell expression of interleukin
(IL)-6 and IL-8 stimulated by phorbol 12-myristate 13-acetate (PMA),
tumor necrosis factor-
, or IL-1
. Nuclear runoff and luciferase
reporter gene assays demonstrate that triptolide inhibits IL-8
transcription. Triptolide also inhibits the transcriptional activation,
but not the DNA binding, of nuclear factor-
B. A cDNA
array and clustering algorithm analysis reveals that triptolide
inhibits expression of the PMA-induced genes tumor necrosis factor-
,
IL-8, macrophage inflammatory protein-2
, intercellular adhesion
molecule-1, integrin
6, vascular endothelial growth factor, granulocyte-macrophage colony-stimulating factor, GATA-3, fra-1, and NF45. Triptolide also inhibits constitutively expressed cell
cycle regulators and survival genes cyclins D1, B1, and A1, cdc-25,
bcl-x, and c-jun. Thus anti-inflammatory, antiproliferative, and proapoptotic properties of triptolide are associated with inhibition of nuclear factor-
B signaling and inhibition of genes known to regulate cell cycle progression and survival.
Tripterygium; interleukin-8; transcription; nuclear
factor-
B; Atlas cDNA array; cyclin
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