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Am J Physiol Lung Cell Mol Physiol 279: L958-L966, 2000;
1040-0605/00 $5.00
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Vol. 279, Issue 5, L958-L966, November 2000

Anti-inflammatory effects of triptolide in human bronchial epithelial cells

Guohua Zhao, Laszlo T. Vaszar, Daoming Qiu, Lingfang Shi, and Peter N. Kao

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-alpha , or IL-1beta . 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-kappa B. A cDNA array and clustering algorithm analysis reveals that triptolide inhibits expression of the PMA-induced genes tumor necrosis factor-alpha , IL-8, macrophage inflammatory protein-2alpha , intercellular adhesion molecule-1, integrin beta 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-kappa B signaling and inhibition of genes known to regulate cell cycle progression and survival.

Tripterygium; interleukin-8; transcription; nuclear factor-kappa B; Atlas cDNA array; cyclin


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