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Titolo:
Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis
Autore:
Kaul, M; Lipton, SA;
Indirizzi:
Brigham & Womens Hosp, CNS Res Inst, Boston, MA 02115 USA Brigham & WomensHosp Boston MA USA 02115 Res Inst, Boston, MA 02115 USA Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA Harvard Univ Boston MA USA 02115 , Program Neurosci, Boston, MA 02115 USA
Titolo Testata:
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
fascicolo: 14, volume: 96, anno: 1999,
pagine: 8212 - 8216
SICI:
0027-8424(19990706)96:14<8212:CAAMIH>2.0.ZU;2-5
Fonte:
ISI
Lingua:
ENG
Soggetto:
COAT PROTEIN GP120; IMMUNODEFICIENCY-VIRUS TYPE-1; CALCIUM-CHANNEL ANTAGONISTS; CORTICAL CELL-CULTURES; 2ND CONSTANT DOMAIN; NITRIC-OXIDE; ENVELOPE PROTEIN; IMMUNOGLOBULIN-G; RECEPTOR CXCR4; RAT;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
48
Recensione:
Indirizzi per estratti:
Indirizzo: Lipton, SA Brigham & Womens Hosp, CNS Res Inst, 75 Francis St, Boston, MA 02115 USA Brigham & Womens Hosp 75 Francis St Boston MA USA 02115 115 USA
Citazione:
M. Kaul e S.A. Lipton, "Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis", P NAS US, 96(14), 1999, pp. 8212-8216

Abstract

HIV-1 glycoprotein gp120 induces injury and apoptosis in rodent and human neurons in vitro and in vivo and is therefore thought to contribute to HIV-associated dementia. In addition to CD4, different gp120 isolates bind to the alpha- or beta-chemokine receptors CXCR4 and CCR5, respectively. These and other chemokine receptors are on brain macrophages/microglia, astrocytes, and neurons. Thus, apoptosis could occur via direct interaction of gp120 with neurons, indirectly via stimulation of glia to release neurotoxic factors, or via both pathways. Here we show in rat cerebrocortical cultures that recapitulate the type and proportion of cells normally found in brain, i.e., neurons, astrocytes, and macrophages/microglia, that the beta-chemokines RANTES (regulated on activation, normal T cell expressed and secreted) and macrophage inflammatory protein (MIP-1 beta) protect neurons from gp120(SF2)-induced apoptosis. The gp120(SF2) isolate prefers binding to CXCR4 receptors, similar to the physiological alpha-chemokine ligands, stromal cell-derived factor (SDF)-1 alpha/beta. SDP-1 alpha/beta failed to prevent gp120(SF2) neurotoxicity, and in fact also induced neuronal apoptosis. We could completely abrogate gp120(SF2)-induced neuronal apoptosis with the tripeptide TKP, which inhibits activation of macrophages/microglia. In contrast, TKPor depletion of macrophages/microglia did not prevent SDF-1 neurotoxicity. Inhibition of p38 mitogen-activated protein kinase ameliorated both gp120(SF2)- and SDF-1-induced neuronal apoptosis, Taken together, these results suggest that gp120(SF2) and SDF-1 differ in the cell type on which they stimulate CXCR4 to induce neuronal apoptosis, but both ligands use the p38 mitogen-activated protein kinase pathway for death signaling. Moreover, gp120(SF2)-induced neuronal apoptosis depends predominantly on an indirect pathwayvia activation of chemokine receptors on macrophages/microglia, whereas SDF-1 may act directly on neurons or astrocytes.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 12/07/20 alle ore 05:32:30