title: TNF-alpha down-regulates CXCR4 expression in primary murine astrocytes.
abstract: 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.
authors.affiliation: Department of Neurosciences, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.  
authors.forename: Y
authors.initials: Y
authors.lastname: Han
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: T
authors.initials: T
authors.lastname: He
authors.forename: R M
authors.initials: RM
authors.lastname: Ransohoff
mesh_terms: D015526:AIDS Dementia Complex / Q000276:immunology / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D001932:Brain Neoplasms / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004660:Encephalitis / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D014409:Tumor Necrosis Factor-alpha; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases