Modulation of P2X7 nucleotide receptor expression by pro- and anti-inflammatory stimuli in THP-1 monocytes

Dynamic regulation of the P2X4 receptor in alveolar macrophages by phagocytosis and classical activation

“…The case for P2X 4 R remains tentative, largely due to the absence of selective P2X 4 R antagonists and the complicating presence of P2X 7 R, which is generally co-expressed with P2X 4 R in macrophages and microglia [3]. P2X 4 R does not appear to couple to any of the same downstream signalling cascades as has been demonstrated for P2X 7 R but studies with P2X 4 R gene-deleted mice have revealed abrogation of tactile allodynia in animal models of inflammatory (formalin-induced) and neuropathic (nerve section) pain via yet-to-be identified alterations in microglial functions [12][13][14].…”

“…Two of these seven members, P2X 4 R and P2X 7 R, have generated increasing interest as potential anti-inflammatory drug targets [2,4,5]. The case for P2X 7 R is now well established: Stimulation of P2X 7 R in activated monocytes, macrophages and microglia leads to rapid release of pro-inflammatory IL-1b and IL-18 cytokines, to phospholipase D activation and, if stimulation is sustained, to apopotosis [1,[3][4][5]. Classical activation of macrophages, generally induced by IFN-g and/or LPS, up-regulates P2X 7 R mRNA and protein levels and functional expression [6,7] and this correlates well with a role for P2X 7 R in bacterial killing [8,9].…”

“…Classical activation of macrophages, generally induced by IFN-g and/or LPS, up-regulates P2X 7 R mRNA and protein levels and functional expression [6,7] and this correlates well with a role for P2X 7 R in bacterial killing [8,9]. Recently, highly selective and potent P2X 7 R antagonists have been identified [10] with one of these showing initial positive results in Phase II clinical trials for rheumatoid arthritis [11]. The case for P2X 4 R remains tentative, largely due to the absence of selective P2X 4 R antagonists and the complicating presence of P2X 7 R, which is generally co-expressed with P2X 4 R in macrophages and microglia [3].…”

“…Alveolar macrophages are the first line of defence in the lung and are known to be among the most highly phagocytic of all tissue macrophages [34]. The rapid and potent increase in functional P2X 4 R expression in response to phagocytosis in these macrophages suggests that this receptor may play an important role in modulating signalling cascades involved in the early stages of macrophage function subsequent to phagocytic stimuli.In contrast to the enhanced functional expression of P2X 4 R in response to phagocytosis, classical activation of alveolar macrophages by IFN-g/LPS or IFN-g/TNF-a resulted in disappearance of functional P2X 4 R. This result is directly opposite to that observed for macrophage P2X 7 R where classical activation (IFN-g/LPS) up-regulates protein and functional expression of this purinergic P2X receptor [6,7]. Classical activation of macrophages is intimately linked to induction of microbicidal activity and several studies have shown that P2X 7 R play a role in killing of Mycobacterium tuberculosis via activation of phospholipase D [8,9,35].…”

“…The case for P2X 7 R is now well established: Stimulation of P2X 7 R in activated monocytes, macrophages and microglia leads to rapid release of pro-inflammatory IL-1b and IL-18 cytokines, to phospholipase D activation and, if stimulation is sustained, to apopotosis [1,[3][4][5]. Classical activation of macrophages, generally induced by IFN-g and/or LPS, up-regulates P2X 7 R mRNA and protein levels and functional expression [6,7] and this correlates well with a role for P2X 7 R in bacterial killing [8,9]. Recently, highly selective and potent P2X 7 R antagonists have been identified [10] with one of these showing initial positive results in Phase II clinical trials for rheumatoid arthritis [11].…”