科研之友
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摘要
Background information. P2x7R is a member of the ionotropic family of purinergic receptors activated by millimolar concentrations of extracellular ATP such as induced by inflammatory stimuli. The receptor is widely expressed in cells of haematopoietic origin such as monocytes, macrophages and microglia. There is growing interest in anta-gonist compounds of the P2x7R since it has been demonstrated to be a viable therapeutic target for inflammatory diseases. Here, we tested the possible P2x7 antagonist effect of MED1101, a newly synthesised dialdehydic compound on U937 monocyte cells. %26lt;br%26gt;Results. Human U937 cells express the full-length P2x7A receptor isoform. Treatment with lipopolysaccharide (LPS), a potent inducer of inflammation, significantly increased the expression of the receptor in the plasma membrane. Importantly, MED1101 induced internalisation of the P2x7R already after 30min incubation in both physiological conditions and in presence of the inflammatory stimulus (LPS) and this effect was observable for up to 12h after its removal. Moreover, MED1101 induced an impairment of monocyte migration/transmigration through direct P2x7R antagonism and subsequent inhibition of the intracellular signal transduction processes of Ca2+ influx and MAPK phosphorylation. %26lt;br%26gt;Conclusions. Our results clearly demonstrate that in U937 monocyte cells MED1101 acts as a P2x7R antagonist through the induction of receptor internalisation and subsequent inhibition of down-stream signal transduction pathways that regulate monocyte migration/transmigration, thus playing a potential therapeutic role in inflammatory diseases.
- 出版日期2013-9
