| 摘要(英) |
Viscum coloratum is a semiparasitic plant, used in traditional Chinese medicine to treat inflammatory diseases. It has been reported that its active component viscolin can inhibit FMLP-activated superoxide anion production and elastase release in human neurtophils. This inhibition is due to a decrease in the activity of type 4 phosphodiesterase (PDE4) activity, and thereby increasing in intracellular cAMP levels. The family of this cAMP-hydrolyzing enzymes consists of four genes named PDE4A, PDE4B, PDE4C and PDE4D, and inhibition of PDE4 is known to produce a wide range of anti-inflammatory response. Thus, the goal of this study is to examine whether viscolin and its structurally similar compounds RX78 and RX116 are similar to rolipram in attenuating inflammatory responses. The results showed that in Raw 264.7 cells and mouse peritoneal macrophages viscolin, RX78 and RX116 significantly inhibit LPS-induced TNF-??release, although the levels of inhibition are not as compelling as that of rolipram. Experiments with bone marrow-derived dendritic cells of wild-type and PDE4KO mice also showed that three compounds exhibited inhibitory effects on LPS-induced TNF-? release. However, the potency was much less than that of rolipram. In addition, three PDE4 isoforms were found to be involved in the LPS/TNF-? response in dendritic cells, with PDE4B and PDE4D the predominant regulators. Using mouse spleen T cells, we observed that IL-2 release in response to CD3 antibody or CD3/CD28 antibody co-stimulation was significantly increased, and the increase with CD3/CD28 antibody co-stimulation was ～20 folds over that with CD3 antibody alone. Such increases could be suppressed by the three compounds to the extents similar to the effect of rolipram. Moreover, the results from PDE4KO T cells indicated that PDE4D is involved in the TCR signaling, while PDE4B contributes to the CD28 co-stimulatory effects. Measurements of cAMP-hydrolyzing activity with recombinant PDE4A and PDE4D revealed that the potency of viscolin, RX78, and RX116 in inhibiting PDE4 activity is 51%, 31% and 45%, respectively. Take togather, these results indicate that the three compounds possess the PDE4 inhibition activity, which is thought to be associated with their anti-inflammatory activites in different cells, in particular of T cells.
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