Expression of macrophage inflammatory protein‐1α and monocyte chemoattractant protein‐1 in glioma‐infiltrating microglia: Involvement of ATP and P2X₇ receptor

Abstract

Chemokines can be produced by gliomas, which mediate the infiltration of microglia, a characteristic feature of glioma-associated neuropathogenesis. ATP that is released at a high level from glioma has been reported to play a regulatory role in chemokine production in cultured glioma cells. The objective of this study was to define the potential role of extracellular ATP in the regulation of macrophage inflammatory protein-1α (MIP-1α) and monocyte chemoattractant protein-1(MCP-1) expression in glioma-associated microglia/macrophages. The results showed that Iba1(+) and ED1(+) microglia existed in the tumor at 3 and 7 day after injection of C6 glioma cells into the rat cerebral cortex (dpi). ED1(+) microglia/macrophages or Iba1(+) microglia in the glioma were also colocalized to MIP-1α- and MCP-1-expressing cells. In vitro study indicated that treatment with ATP and BzATP (an agonist for ATP ionotropic receptor P2X₇R) caused an increase in the intracellular levels of microglial MIP-1α and MCP-1. By using an extracellular Ca(2+) chelator (EGTA) and P2X₇R antagonists, oxidized ATP (oxATP) and brilliant blue G (BBG), we demonstrated that BzATP-induced production of MIP-1α and MCP-1 levels was due to P2X₇R activation and Ca(2+) -dependent regulation. Coadministration of C6 glioma cells and oxATP into the rat cerebral cortex resulted in a reduction of MIP-1α- and MCP-1-expressing microglia/macrophages. We suggest, based on the results from in vivo and in vitro studies, that a massive amount of ATP molecules released in the glioma tumor site may act as the regulator with P2X₇R signaling that increases MIP-1α and MCP-1 expression in tumor-infiltrating microglia/macrophages.

The expression of P2X7receptors in EPCs and their potential role in the targeting of EPCs to brain gliomas

“…6A). It is reported that P2X 7 receptors could regulate the expression of MCP-1, 28,29 which plays a key role in the recruitment of progenitor cells. 30 So, we also detected the expression of MCP-1 in BBG treated or untreated group.…”

Distribution and characterization of tumor-associated macrophages/microglia in rat C6 glioma

“…ED1, which is mainly found in phagocytosing macrophages and reactive microglia, is a lysosomal membrane protein. Macrophages with ED1 can be observed in the majority of brain tumors, as well as in gliomas (18). Cluster of differentiation 8 (CD8) was traditionally recognized as a marker that is mainly expressed in cytotoxic T cells and natural killer cells (19 (21).…”

Purinergic signalling and cancer

“…P2X7 receptor agonists produced cell death in the glioma radiosensitive cell line M059J, but the radioresistant glioma cell line, U138-MG, presented resistance to death when treated with either ATP or BzATP [598]. ATP released from glioma tumour cells may act as the regulator, via P2X7 receptor signalling, that increases macrophage inflammatory protein-1α and monocyte chemoattractant protein-1 expression in tumour-infiltrating microglia [599]. It was claimed that BzATP-mediated calcium signalling in C6 cells was mediated by P2Y (perhaps P2Y 2 ), rather than P2X7 receptors [36].…”