Astrocytes are specialized cells of the CNS that are implicated in the pathogenesis of multiple sclerosis and experimental allergic encephalomyelitis. In acute and relapsing-remitting experimental allergic encephalomyelitis, the neutrophil chemoattractant CXC chemokines macrophage-inflammatory protein (MIP)-2 and KC are associated with reactive astrocytes in the parenchyma. In vitro treatment of primary astrocyte cultures with nanomolar concentrations of MIP-2 or KC markedly up-regulated expression of the monocyte/T cell chemoattractants monocyte chemoattractant protein-1, inflammatory protein-10, and RANTES by a mechanism that includes stabilization of mRNA. Production of TNF-alpha and IL-6 transcripts were also noted, as was autocrine induction of MIP-2 and KC message. In addition, low levels of MIP-1alpha and MIP-1beta were induced following treatment with MIP-2 or KC. These effects are specific to astrocytes as MIP-2 treatment of microglial cells failed to elicit chemokine production. The astrocyte chemokine receptor for MIP-2 has 2.5 nM affinity for ligand. Astrocytes from CXCR2-deficient mice still respond to KC and MIP-2, indicating the presence of an alternative or novel high affinity receptor for these ligands. We propose that this KC/MIP-2 chemokine cascade may contribute to the persistence of mononuclear cell infiltration in demyelinating autoimmune diseases.