P2X7-like receptor activation in astrocytes increases chemokine monocyte chemoattractant protein-1 expression via mitogen-activated protein kinase

Leukocyte infiltration in the CNS after trauma or inflammation is triggered in part by upregulation of the chemokine, monocyte chemoattractant protein -1 (MCP-1), in astrocytes. However the signals that induce the upregulation of MCP-1 in astrocytes are unknown. We have investigated the roles for ATP P2X7 receptor activation because ATP is an intercellular signaling transmi tter that is released in both trauma and inflammation and P2X7 receptors ar e involved in immune system signaling. Astrocytes in primary cell culture a nd acutely isolated from the hippocampus were immunopositive for P2X7 recep tors. In astrocyte cultures, application of the selective P2X7 agonist, ben zoyl-benzoyl ATP (Bz-ATP), activated MAP kinases extracellular signal recep tor-activated kinase 1 (ERK1), ERK2, and p38. Purinergic antagonists depres sed this activation with a profile suggesting P2X7 receptors. Bz-ATP also i ncreased MCP-1 expression in cultured astrocytes, and again P2X7 antagonist s prevented this increase. Blocking either the ERK1/ERK2 or the p38 pathway (with PD98059 or SB203580, respectively) significantly inhibited Bz-ATP-in duced MCP-1 expression. Coapplication of both antagonists caused a greater depression. We also tested the roles for ATP receptor activation in inducin g MCP-1 upregulation in corticectomy, an in vivo model of trauma. This mode l of cortical trauma was previously shown to increase MCP-1 expression in v ivo principally in astrocytes. Suramin, a wide-spectrum purinergic receptor antagonist, significantly depressed the rapid (3 hr) trauma-induced increa se in MCP-1 mRNA. These data indicate that purinergic transmitter receptors in astrocytes are important in regulating chemokine synthesis. The regulat ion of MCP-1 in astrocytes by ATP may be important in mediating communicati on with hematopoietic inflammatory cells.