title: Induction of tumor necrosis factor alpha in human neuronal cells by extracellular human T-cell lymphotropic virus type 1 Tax.
abstract: To examine the role of human T-lymphotropic virus type 1 (HTLV-1) Tax1 in the development of neurological disease, we studied the effects of extracellular Tax1 on gene expression in NT2-N cells, postmitotic cells that share morphologic, phenotypic, and functional features with mature human primary neurons. Treatment with soluble HTLV-1 Tax1 resulted in the induction of tumor necrosis factor alpha (TNF-alpha) gene expression, as detected by reverse-transcribed PCR and by enzyme-linked immunosorbent assay. TNF-alpha induction was completely blocked by clearance with anti-Tax1 monoclonal antibodies. Furthermore, cells treated with either a mock bacterial extract or with lipopolysaccharide produced no detectable TNF-alpha. Synthesis of TNF-alpha in response to soluble Tax1 occurred in a dose-dependent fashion between 0.25 and 75 nM and peaked within 6 h of treatment. Interestingly, culturing NT2-N cells in the presence of soluble Tax1 for as little as 5 min was sufficient to result in TNF-alpha production, indicating that the induction of TNF-alpha in NT2-N does not require Tax1 to be continually present in the culture medium. Treatment of the undifferentiated parental embryonal carcinoma cell line NT2 with soluble Tax1 did not result in TNF-alpha synthesis, suggesting that differentiation-dependent, neuron-specific factors may be required. These results provide the first experimental evidence that neuronal cells are sensitive to HTLV-1 Tax1 as an extracellular cytokine, with a potential role in the pathology of HTLV-1-associated/tropical spastic paraparesis.
authors.affiliation: Division of Transfusion Transmitted Diseases, Food and Drug Administration, Rockville, Maryland, USA. epc@helix.nih.gov
authors.forename: E P
authors.initials: EP
authors.lastname: Cowan
authors.forename: R K
authors.initials: RK
authors.lastname: Alexander
authors.forename: S
authors.initials: S
authors.lastname: Daniel
authors.forename: F
authors.initials: F
authors.lastname: Kashanchi
authors.forename: J N
authors.initials: JN
authors.lastname: Brady
mesh_terms: D002454:Cell Differentiation; D002460:Cell Line; D016356:Gene Products, tax / Q000502:physiology*; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D008938:Mitosis; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D016356:Gene Products, tax; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha