title: Gp120-mediated cytotoxicity of human brain microvascular endothelial cells is dependent on p38 mitogen-activated protein kinase activation.
abstract: Breakdown of the blood-brain barrier has been shown to contribute to neurological disorders that are prevalent in human immunodeficiency virus type 1 (HIV-1)-infected individuals, but the mechanisms involved in HIV-1-associated blood-brain barrier dysfunction remain incompletely understood. Using human brain microvascular endothelial cells (HBMECs) that constitute the blood-brain barrier, the authors determined the cytotoxic effects of gp120 on HBMECs. The authors showed that gp120 induced cytotoxicity of HBMECs derived from children, which required cotreatment with interferon (IFN)-gamma. IFN-gamma treatment exhibited up-regulation of the chemokine receptors CCR3 and CCR5 in children's HBMECs. In contrast, HBMECs isolated from adults were not responsive to gp120-mediated cytotoxicity. Peptides of gp120 representing binding regions for CD4 and chemokine receptors as well as CD4 antibody inhibited gp120-mediated cytotoxicity of HBMECs. RANTES, as expected, inhibited M-tropic gp120-mediated HBMEC cytotoxicity, whereas stromal cell-derived factor (SDF)-1alpha failed to inhibit T-tropic gp120-mediated cytotoxicity. Of interest, gp120 peptides representing non-CD4/non-chemokine receptor binding regions inhibited gp120-mediated HBMEC cytotoxicity. In addition, the authors showed that gp120-mediated HBMEC cytotoxicity involved p38 mitogen-activated protein kinase pathway. Taken together, these findings showed that gp120, in the presence of IFN-gamma, can cause dysfunction of the blood-brain barrier endothelium via MAPK pathways involving several gp120-HBMEC interactions.
authors.affiliation: Division of Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Naveed Ahmed
authors.initials: NA
authors.lastname: Khan
authors.forename: Francescopaolo
authors.initials: F
authors.lastname: Di Cello
authors.forename: Monique
authors.initials: M
authors.lastname: Stins
authors.forename: Kwang Sik
authors.initials: KS
authors.lastname: Kim
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000201:enzymology / Q000821:virology*; D002478:Cells, Cultured; D002648:Child; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology / Q000821:virology*; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D015497:HIV-1; D006801:Humans; D007371:Interferon-gamma / Q000627:therapeutic use; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics / Q000633:toxicity; D054390:Receptors, CCR2; D054397:Receptors, CCR3; D019713:Receptors, CCR5 / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics; D019707:Receptors, Chemokine / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; C515334:CCR2 protein, human; C515350:CCR3 protein, human; D015699:HIV Envelope Protein gp120; D010446:Peptide Fragments; D054390:Receptors, CCR2; D054397:Receptors, CCR3; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases