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Published online before print February 6, 2007

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(Journal of Leukocyte Biology. 2007;81:1276-1286.)
© 2007 by Society for Leukocyte Biology

(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^,1, Chien-Chang Shen^,, Ming-Hsi Wu^*, Jyh-Fei Liao^*, Yun-Lian Lin^,, Chieh-Fu Chen^*,|| and Wei-Jern Tsai^*,,,1,2

^* 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, Qingdao, Republic of China

² Correspondence: Room 517, Laboratory of Biochemistry, National Research Institute of Chinese Medicine, No. 155-1, Sec. 2, Li-Nung St., Shih-Pai, 112, Taipei, Taiwan, R.O.C. E-mail: wjtsai{at}nricm.edu.tw

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