title: HIV-1-infected and/or immune-activated macrophage-secreted TNF-alpha affects human fetal cortical neural progenitor cell proliferation and differentiation.
abstract: Neurogenesis, tied to the proliferation, migration and differentiation of neural progenitor cells (NPC) is affected during neurodegenerative diseases, but how neurogenesis is affected during HIV-1 associated dementia (HAD) has not been fully addressed. Here we test the hypothesis that HIV-1-infected and/or immune-activated brain macrophages affect NPC proliferation and differentiation through the regulation of cytokines. We showed that human monocyte-derived macrophages (MDM) conditioned medium (MCM) induces a dose dependent increase in NPC proliferation. Conditioned media from lipopolysaccharide (LPS)-activated MDM (LPS-MCM) or HIV-infected MCM (HIV-MCM) induced a profound increase in NPC proliferation. HIV-infected and LPS-activated MCM (HIV+LPS-MCM) induced the most robust increase in NPC proliferation. Moreover, LPS-MCM and HIV+LPS-MCM decreased beta-III-tubulin and increased GFAP expression, demonstrating an induction of gliogenesis and inhibition of neurogenesis. The increase of NPC proliferation and gliogenesis correlated with increases in production of TNF-alpha by infected/activated MDM. Although both IL-1beta and TNF-alpha induced NPC proliferation and gliogenesis, these effects were only partially abrogated by soluble TNF-alpha receptors R1 and R2 (TNF-R1R2), but not by the IL-1 receptor antagonist (IL-1ra). This indicated that the HIV-1-infected/LPS-activated MCM-mediated effects were, in part, through TNF-alpha. These observations were confirmed in severe combined immunodeficient (SCID) mice with HIV-1 encephalitis (HIVE). In these HIVE mice, NPC injected with HIV-infected MDM showed more astrocyte differentiation and less neuronal differentiation compared to NPC injection alone. These observations demonstrated that HIV-1-infected and immune-activated MDM could affect neurogenesis through induction of NPC proliferation, inhibition of neurogenesis, and activation of gliogenesis.
authors.affiliation: Laboratory of Neurotoxicology, University of Nebraska Medical Center, Omaha, Nebraska 68190-5880, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.forename: Nicholas
authors.initials: N
authors.lastname: Whitney
authors.forename: Yumei
authors.initials: Y
authors.lastname: Wu
authors.forename: Changhai
authors.initials: C
authors.lastname: Tian
authors.forename: Huanyu
authors.initials: H
authors.lastname: Dou
authors.forename: You
authors.initials: Y
authors.lastname: Zhou
authors.forename: Jialin
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005333:Fetus; D005786:Gene Expression Regulation / Q000187:drug effects; D015658:HIV Infections / Q000473:pathology / Q000628:therapy; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000737:chemistry / Q000378:metabolism* / Q000821:virology; D051379:Mice; D016513:Mice, SCID; D009419:Nerve Tissue Proteins / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects*; D013936:Thymidine / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; D014409:Tumor Necrosis Factor-alpha; D013936:Thymidine