Deng-hai Zhang [1,2], Anthony Marconi, Li-Min Xu, Chun-xin Yang [3], Guo-wu Sun [4], Xiao-ling Feng [4], Shu-min Xu [2], Chang-quan Ling [5], Wan-zhang Qin [3], Georges Uzan [1], Patrizia d'Alessio [1]

Introduction: Chemical compounds derived from plants used in traditional medicine to cure disease, are an important source for the development of new active pharmaceutical molecules. Using such a strategy, tripterine, a triterpenoid from the Celastrae family, extracted from the Chinese herbal plant Tripterygium wilfordii Hook F (TWHF) (Chou and Mei, 1936), has attracted much interest (Calixto et al, 2004). TWHF (whose chinese name "Lei Gong Teng" which means "thunder god vine") has been used for thousands of years in China as a remedy against arthritis and other autoimmune diseases (Guo et al, 1981; Lipsky and Tao, 1997). The in vivo anti-inflammatory effects of tripterine had been demonstrated in animal models of collagen-induced arthritis (Li et al., 1997), Alzheimer's disease (Allison et al., 2001), as well as nephritis in lupus-like mice. Tripterine, a chemical compound of Chinese herbal plant Triptergium wilfordii Hook F, thus displays anti-inflammatory properties. Adhesion molecules expressed by vascular endothelium in response to cytokine stimulation play a key role in the inflammatory response. They recruit circulating leukocytes for tissue immune survey.

Materials Methods and Results: We examined the effects of tripterine on the expression of cell adhesion molecules and adhesiveness of leukocytes in Human Umbilical Vein Endothelial Cells (HUVEC) stimulated by pro-inflammatory cytokines. Pre-treatment with tripterine at non-toxic concentrations for six hours, concentration-dependently inhibited expression of E-selectin, Vascular Cell Adhesion Molecule-1 (VCAM-1) and Inter-Cellular Adhesion Molecule-1 (ICAM-1) in HUVEC stimulated by Tumor Necrosis Factor-alpha (TNF-alpha). Inhibition by tripterine at the non-toxic concentration of 200 nmol/L was almost complete for VCAM-1 and ICAM-1 and 70% for E-selectin (IC50=100nM). This effect is fairly more important than that obtained by the treatment of endothelial cells with dexamethasone, ibuprofen, methotrexate or probucol at 1 mmol/L. Other pro-inflammatory cytokines, such as interleukin-1beta (IL-1beta) and interferon-gamma (IFN-gamma) were also significantly inhibited by tripterine in inducing cell adhesion molecules. Moreover, tripterine extensively inhibited adhesion of human monocytes and T lymphocytes by TNF-alpha-stimulated HUVEC. An NF-kappaB dependent mechanism of action was demonstrated underlying the observed effects. Thus, tripterine, already known for its capacity to inhibit pro-inflammatory cytokines in monocytes, also displays a negative regulation of cytokine-induced adhesion molecule expression and adhesiveness in endothelium.

Conclusion: The recurrent clinical evidence of a predisposing link between long lasting inflammatory disease and the development of tissue degeneration or cancer is here addressed by a cell biology

in vitro

validation. These results enable us to further investigate and propose a pharmacological anti-inflammatory approach to tissue senescence in diseases generated by endothelial dysfunction.

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