Abstract
The flower buds of Daphne genkwa Sieb. et Zucc. have been used as a traditional Chinese medicine although their functional mechanisms have not been discovered yet. We have studied the potential effects of the plant extracts on natural killer (NK) cell activation, and isolated an active fraction. Genkwadaphnin (GD-1) displayed a potent efficacy to induce IFN-γ transcription in NK cells with concentration- and time-dependent manners. GD-1 treatment triggered the phosphorylation of PKD1, a member of PKC family, MEK and ERK, resulting in IKK activation to induce IκB degradation, and the nuclear localization of p65, an NF-κB subunit, which regulates IFN-γ transcription. GD-1 effect on IFN-γ production was blocked by the addition of Rottlerin, a PKC inhibitor, CID 755673, a PKD inhibitor, or Bay11-7082, an IKKα inhibitor. The nuclear localization of p65 was also inhibited by the kinase inhibitors. Secreted IFN-γ activates STAT1 phosphorylation as autocrine-loops to sustain its secretion. GD-1 induced the phosphorylation of STAT1 probably through the increase of IFN-γ. STAT1 inhibitor also abrogated the sustained IFN-γ secretion. These results suggest that GD-1 is involved in the activation of PKD1 and/or ERK pathway, which activate NK-κB triggering IFN-γ production. As positive feedback loops, secreted IFN-γ activates STAT1 and elongates its production in NK-92 cells.
Highlights
The flower buds of Daphne genkwa Siebold et Zuccarini (Thymelaeaceae) is a traditional Chinese toxic herb, which is commonly used for diuretic, antitussive, expectorant, edema, and asthma treatments their specific biological activities have not been defined yet
Among ten fractions (F3-A to J), Fraction 3 (F3)-C was separated by the succession of one more round of silica gel eluted with hexane/EtOAc (15:1), and RP C-18 eluted with MeOH/H2O (3:1) to give GD-1
The treatment of single fraction, GD-1 or yuanhuacine, was able to induce of IFN-c production, similar to the level induced by the treatment of total extracts from the Daphne genkwa plant (Fig. 1B)
Summary
The flower buds of Daphne genkwa Siebold et Zuccarini (Thymelaeaceae) is a traditional Chinese toxic herb, which is commonly used for diuretic, antitussive, expectorant, edema, and asthma treatments their specific biological activities have not been defined yet. IFN-c Production by Genkwadaphnin on malignant ascites and solid tumors [1,2,3]. Genkwadaphnin (GD-1) and yuanhuacine, have been isolated from the dried flower buds to possess significant anti-tumor activities via the suppression of DNA synthesis and the activation of apoptotic pathways against leukemic cell lines [4, 5]. Yuanhuacine has showed cytotoxic activities against solid tumor cell lines like MCF-7 and Colo 205 [6]. CD56dimCD16+ NK cells occupy the majority of blood and spleen NK cells, which are highly cytotoxic but have low levels of cytokine secretion. Most NK cells in the lymph node are CD56brightCD162 with poor cytotoxic capability but produce large amount of proinflammatory cytokines such as IFN-c, TNF, and GM-CSF. CD56dimCD16+ NK cells secrete IFN-c after activation. The ability to secrete IFN-c made NK cells as a regulator of the coordinated activation of innate and adaptive immunity
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