CXC chemokine receptor 4 (CXCR4) is a co-receptor for human immunodeficiency virus (HIV) infection and is believed to be involved in the pathogenesis of AIDS-associated neurologic disorders and brain tumors. The physiological roles of CXCR4 in developmental patterning of the nervous and hematopoietic system; gastrointestinal angiogenesis; and cardiac organogenesis were established by studies in gene-targeted mice. Studies on CXCR4 expression and regulation in neuroepithelial cells are fundamental for understanding its physiopathologic roles in the central nervous system (CNS). We show here that CXCR4 expression by primary mouse astrocytes is suppressed by exposure to tumor necrosis factor-alpha (TNF-alpha). TNF-alpha caused a pronounced down-regulation of CXCR4 mRNA in a dose- and time-dependent manner. TNF-alpha-mediated decrease of CXCR4 mRNA accumulation resulted in decreased CXCR4 protein expression. As a result, the ability of stromal cell-derived factor-1alpha (SDF-1alpha) to induce activation of MAP kinases, Erk1/2 was impaired. The half life of CXCR4 mRNA in the presence and absence of TNF-alpha stimulation was comparable, suggesting that TNF-alpha down-regulated CXCR4 mRNA at the transcriptional level. These results suggest that TNF-alpha could modulate HIV and brain tumor pathogenesis and immune-mediated inflammation in the central nervous system (CNS) by regulation of CXCR4 expression.