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Published online before print February 6, 2007

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0106056

Received for publication January 24, 2006.
Revised December 11, 2006.
Accepted for publication January 1, 2007.

Article

(S)-Armepavine inhibits human peripheral blood mononuclear cell activation by regulating Itk and PLC activation in a PI-3K-dependent manner

Chih-Peng Liu ^*, Yuh-Chi Kuo , Chien-Chang Shen , Ming-Hsi Wu ^*, Jyh-Fei Liao ^*, Yun-Lian Lin , Chieh-Fu Chen ^*||, and Wei-Jern Tsai ^*@

*Institute of Pharmacology, National Yang-Ming University, Taipei, Republic of China; Institute of Life Science, Fu-Jen University, Taipei, Republic of China; National Research Institute of Chinese Medicine, Taipei, Republic of China; National Tai-Tung University, Taitung, Taiwan, Republic of China; and ^||Qing-Dao University, Republic of China

^@ To whom correspondence should be addressed. E-mail: wjtsai{at}nricm.edu.tw.

	Abstract

Chinese herbs are useful edible and medicinal plants for their immune modulatory functions. We have proven that (S)-armepavine (C₁₉H₂₃O₃N; MW313) from Nelumbo nucifera inhibits the proliferation of human PBMCs activated with PHA and improves autoimmune diseases in MRL/MpJ-lpr/lpr mice. In the present study, the pharmacological activities of (S)-armepavine were evaluated in PHA-activated PBMCs. The results showed that (S)-armepavine suppressed PHA-induced PBMC proliferation and genes expression of IL-2 and IFN- without direct cytotoxicity. Inhibition of NF-AT and NF-B activation suggested phospholipase C (PLC)-mediated Ca²⁺ mobilization and protein kinase C activation were blocked by (S)-armepavine. Phosphorylation of PLC is regulated by lymphocyte-specific kinase (Lck), ZAP-70, and IL-2-inducible T cell kinase (Itk). We found (S)-armepavine inhibited PHA-induced phosphorylation of Itk and PLC efficiently but did not influence Lck or ZAP-70 phosphorylation. In addition, ZAP-70-mediated pathways, such as the association of linker for activation of T cells with PLC and activation of ERK, were also intact in the presence of (S)-armepavine. Finally, reduction of phosphoinositide 3,4,5-trisphosphate formation and Akt phosphorylation suggested that (S)-armepavine inhibited Itk, and PLC phosphorylation might be a result of the influence of PI-3K activation. Addition of exogenous IL-2 or PMA/A23187 rescued PBMC proliferation in the presence of (S)-armepavine. Therefore, we concluded that (S)-armepavine inhibited PHA-induced cell proliferation and cytokine production in a major way by blocking membrane-proximal effectors such as Itk and PLC in a PI-3K-dependent manner.

Key Words: lymphocytes • proliferation • phytohemagglutinin • cytokines