TNF-alpha down-regulates CXCR4 expression in primary murine astrocytes

CXC chemokine receptor 4 (CXCR4) is a co-receptor for human immunodeficienc y 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 hematopoieti c system: gastrointestinal angiogenesis; and cardiac organogenesis were est ablished by studies in gene-targeted mice. Studies on CXCR4 expression and regulation in neuroepithelial cells are fundamental for understanding its p hysiopathologic roles in the central nervous system (CNS). We show here tha t CXCR4 expression by primary mouse astrocytes is suppressed by exposure to tumor necrosis factor-alpha (TNF-alpha). TNF-alpha caused a pronounced dow n-regulation of CXCR4 mRNA in a dose- and time-dependent manner. TNF-alpha -mediated decrease of CXCR4 mRNA accumulation resulted in decreased CXCR4 p rotein expression. As a result, the ability of stromal cell-derived factor- 1 alpha (SDF-1 alpha) to induce activation of MAP kinases, Erk 1/2 was impa ired. 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 cou ld modulate HIV and brain tumor pathogenesis and immune-mediated inflammati on in the central nervous system (CNS) by regulation of CXCR4 expression. ( C) 2001 Elsevier Science B.V. All rights reserved.