title: 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.
authors.affiliation: Department of Life Sciences, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Kuan-Min
authors.initials: KM
authors.lastname: Fang
authors.forename: Ying-Lan
authors.initials: YL
authors.lastname: Wang
authors.forename: Ming-Chao
authors.initials: MC
authors.lastname: Huang
authors.forename: Synthia H
authors.initials: SH
authors.lastname: Sun
authors.forename: Henrich
authors.initials: H
authors.lastname: Cheng
authors.forename: Shun-Fen
authors.initials: SF
authors.lastname: Tzeng
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D054405:Chemokine CCL3 / Q000096:biosynthesis*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D005786:Gene Expression Regulation; D005910:Glioma / Q000276:immunology / Q000378:metabolism*; D007150:Immunohistochemistry; D017628:Microglia / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058469:Receptors, Purinergic P2X / Q000378:metabolism*
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D058469:Receptors, Purinergic P2X; D000255:Adenosine Triphosphate