title: Astrocytic alterations induced by HTLV type 1-infected T lymphocytes: a role for Tax-1 and tumor necrosis factor alpha.
abstract: In the neurological disease associated with HTLV-1 infected T lymphocytes infiltrated within the CNS are suspected of playing a prominent role in pathogenesis via inflammatory cytokines and the viral protein Tax-1. We hypothesized that T lymphocytes initiate functional perturbation in astrocytes, resulting in neuronal alteration as glial cells have a crucial role in CNS homeostasis. In particular, astrocytes manage the steady state level of glutamate and continuously provide metabolite precursors to neurons and oligodendrocytes. Using a model system of HTLV-1-infected T cells-astrocytes interaction, we show that after contact with T cells, astrocyte acquire a phenotype typical of gliosis: secretion of proinflammatory cytokines (TNF-alpha, IL-1alpha, IL-6) and matrix metalloproteinases (MMP-9, MMP-3). The concomitant increase in the expression of MMPs and of their endogenous inhibitors (TIMP-1 and TIMP-3) suggests a perturbation in MMP/TIMP balance. This may alter the extracellular matrix and, in turn, the cell environment. At a functional level, glutamate transport and catabolism are impaired in astrocytes. A decrease in glutamate uptake is associated with downregulated expression of glutamate transporters GLAST and GLT1. The expression of astrocytic enzyme of glutamate metabolism is modified with up-regulation of glutamine synthetase and down-regulation of glutamate dehydrogenase. The involvement of Tax-1 in these alterations, directly or indirectly via TNF-alpha, is shown. Altered glutamate uptake and catabolism associated with impairment in cell connectivity via MMP/TIMP imbalance could compromise the functional integrity of the CNS in general and that of neurons and oligodendrocytes in particular.
authors.affiliation: U433 INSERM, Faculté de Médecine R. Laënnec, 69372 Lyon, France.
authors.forename: R
authors.initials: R
authors.lastname: Szymocha
authors.forename: H
authors.initials: H
authors.lastname: Akaoka
authors.forename: C
authors.initials: C
authors.lastname: Brisson
authors.forename: P
authors.initials: P
authors.lastname: Beurton-Marduel
authors.forename: A
authors.initials: A
authors.lastname: Chalon
authors.forename: A
authors.initials: A
authors.lastname: Bernard
authors.forename: M
authors.initials: M
authors.lastname: Didier-Bazes
authors.forename: M F
authors.initials: MF
authors.lastname: Belin
authors.forename: P
authors.initials: P
authors.lastname: Giraudon
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology* / Q000502:physiology / Q000821:virology; D002460:Cell Line; D016356:Gene Products, tax / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D015493:Paraparesis, Tropical Spastic / Q000473:pathology* / Q000821:virology; D051381:Rats; D013601:T-Lymphocytes / Q000378:metabolism* / Q000821:virology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016356:Gene Products, tax; D005971:Glutamates; D014409:Tumor Necrosis Factor-alpha