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(S)‐Armepavine inhibits human peripheral blood mononuclear cell activation by regulating Itk and PLCγ activation in a PI‐3K‐dependent manner
Author(s) -
Liu ChihPeng,
Kuo YuhChi,
Shen ChienChang,
Wu MingHsi,
Liao JyhFei,
Lin YunLian,
Chen ChiehFu,
Tsai WeiJern
Publication year - 2007
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0106056
Subject(s) - phosphorylation , peripheral blood mononuclear cell , microbiology and biotechnology , biology , mapk/erk pathway , kinase , t cell , protein kinase b , immune system , immunology , biochemistry , in vitro
Chinese herbs are useful edible and medicinal plants for their immune modulatory functions. We have proven that (S)‐armepavine (C 19 H 23 O 3 N; 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‐γ without direct cytotoxicity. Inhibition of NF‐AT and NF‐κB activation suggested phospholipase Cγ (PLCγ)‐mediated Ca 2 + mobilization and protein kinase C activation were blocked by (S)‐armepavine. Phosphorylation of PLCγ 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 PLCγ 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 PLCγ 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 PLCγ 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 PLCγ in a PI‐3K‐dependent manner.