Astrocytes respond to stimulation with the chemokine RANTES (regulated on activation, normal T cell expressed) by production of a series of cytokines and chemokines, including tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1). In the present study we demonstrate that RANTES induces TNF, which in turn stimulates subsequent production of MCP-1. TNF-R1 (p55) serves as the principal receptor responsible for MCP-1 synthesis. The results define an astrocyte proinflammatory cascade that amplifies synthesis of proinflammatory mediators. The implications of these findings to inflammatory diseases of the central nervous system are discussed. © 2003 Wiley-Liss, Inc.