Fibroblast growth factor modulates HIV coreceptor CXCR4 expression by neural cells. HNRC Group.
Recent studies suggest that the chemokine receptor CXCR4 may be involved in mediating the neurodegenerative process in the brains of patients with acquired immunodeficiency disease (AIDS). In this context, we hypothesize that neurotrophic factors, such as fibroblast growth factor (FGF), might protect against human immunodeficiency virus (HIV)-mediated neurotoxicity via regulating the expression of CXCR4 in neural cells. For this purpose, levels of CXCR4 were determined in neuronal and glial cell lines after FGF1 and 2 treatment. In addition, levels of CXCR4 immunoreactivity were associated with levels of FGF1 immunoreactivity in the brains of HIV-positive patients. These studies showed that neuronal CXCR4 levels decreased in a dose-dependent manner after exposure to FGF. Conversely, glial CXCR4 was increased in a dose-dependent manner after FGF2 treatment. These effects were dependent on the FGF receptor tyrosine kinase signaling pathway, because FGF-induced effects on CXCR4 were blocked by the tyrosine kinase inhibitor, 5'-deoxy-5'methylthioadenosine, or by anti-FGF receptor antibody. Stromal cell-derived factor-1, the ligand for CXCR4, and HIV gp120 neurotoxicity was attenuated by FGF1 in a dose-dependent manner in vitro, further supporting physiological relevance. In the brains of AIDS patients, the levels of neural CXCR4 immunoreactivity were inversely associated with FGF levels. Taken together, these results support the possibility that the neuroactive effects of FGF in HIV encephalitis might be mediated through regulation of the expression of CXCR4.
Sanders
V J
VJ
Department of Neurosciences, University of California, San Diego, La Jolla 92093-0624, USA.
Everall
I P
IP
Johnson
R W
RW
Masliah
E
E
D000163:Acquired Immunodeficiency Syndrome / Q000378:metabolism / Q000473:pathology; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000502:physiology*; D006678:HIV / Q000378:metabolism*; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000378:metabolism*
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D015699:HIV Envelope Protein gp120; D009498:Neurotoxins; D019718:Receptors, CXCR4; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D005346:Fibroblast Growth Factors