title: Platelet-derived growth factor (PDGF)-BB-mediated induction of monocyte chemoattractant protein 1 in human astrocytes: implications for HIV-associated neuroinflammation.
abstract: Chemokine (C-C motif) ligand 2, also known as monocyte chemoattractant protein 1 (MCP-1) is an important factor for the pathogenesis of HIV-associated neurocognitive disorders (HAND). The mechanisms of MCP-1-mediated neuropathogenesis, in part, revolve around its neuroinflammatory role and the recruitment of monocytes into the central nervous system (CNS) via the disrupted blood-brain barrier (BBB). We have previously demonstrated that HIV-1/HIV-1 Tat upregulate platelet-derived growth factor (PDGF)-BB, a known cerebrovascular permeant; subsequently, the present study was aimed at exploring the regulation of MCP-1 by PDGF-BB in astrocytes with implications in HAND. Specifically, the data herein demonstrate that exposure of human astrocytes to HIV-1 LAI elevated PDGF-B and MCP-1 levels. Furthermore, treating astrocytes with the human recombinant PDGF-BB protein significantly increased the production and release of MCP-1 at both the RNA and protein levels. MCP-1 induction was regulated by activation of extracellular-signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinases and phosphatidylinositol 3-kinase (PI3K)/Akt pathways and the downstream transcription factor, nuclear factor κB (NFκB). Chromatin immunoprecipitation (ChIP) assays demonstrated increased binding of NFκB to the human MCP-1 promoter following PDGF-BB exposure. Conditioned media from PDGF-BB-treated astrocytes increased monocyte transmigration through human brain microvascular endothelial cells (HBMECs), an effect that was blocked by STI-571, a tyrosine kinase inhibitor (PDGF receptor (PDGF-R) blocker). PDGF-BB-mediated release of MCP-1 was critical for increased permeability in an in vitro BBB model as evidenced by blocking antibody assays. Since MCP-1 is linked to disease severity, understanding its modulation by PDGF-BB could aid in understanding the proinflammatory responses in HAND. These results suggest that astrocyte activation by PDGF-BB exaggerates monocyte recruitment into the brain via MCP-1 and underscores the critical role astrocytes play in HAND.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Crystal
authors.initials: C
authors.lastname: Bethel-Brown
authors.forename: Honghong
authors.initials: H
authors.lastname: Yao
authors.forename: Guoku
authors.initials: G
authors.lastname: Hu
authors.forename: Shilpa
authors.initials: S
authors.lastname: Buch
mesh_terms: D000704:Analysis of Variance; D000906:Antibodies / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects* / Q000821:virology; D000077214:Becaplermin; D001808:Blood Vessels / Q000166:cytology; D002465:Cell Movement; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015967:Gene Expression Regulation, Viral / Q000187:drug effects / Q000502:physiology*; D015658:HIV Infections; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D009154:Mutation / Q000235:genetics; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D014162:Transfection
chemical_list: D000906:Antibodies; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D000077214:Becaplermin; D020929:Mitogen-Activated Protein Kinase Kinases