title: Modulation of glutathione intracellular levels alters the spontaneous proliferation of lymphocyte from HTLV-1 infected patients.
abstract: The human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus associated with neoplasias and inflammatory diseases, such as adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1-infected individuals present a spontaneous T lymphocyte proliferation. This phenomenon is related to the HTLV-1-proviral load and the persistence of the infection. Viral proteins induce many cellular mediators, which can be associated with the abnormal cellular proliferation. The intracellular levels of glutathione (GSH) are important to modulate the cellular proliferation. The aim of this study was to investigate the correlation between the modulation of intracellular GSH levels and the spontaneous lymphocyte proliferation during the HTLV-1 infection. Intracellular GSH level can be modulated by using dl-buthionine-[S,R]-sulfoximine (BSO, GSH synthesis inhibitor) and N-acetylcysteine (NAC, peptide precursor). Our results demonstrated that BSO was capable of inducing a decrease in the spontaneous proliferation of PBMC derived from HTLV-1 carriers. On the other hand, the GSH precursor induces an increase in mitogen-stimulated cellular proliferation in infected and uninfected individuals. Similar results were observed by the inhibition of ABCC1/MRP1 protein, augmenting the mitogen-induced proliferation. This effect can be related with an increase in the GSH levels since ABCC1/MRP1 transports GSH to the extracellular medium. There was a significant difference on the expression of CD69 and CD25 molecules during the lymphocyte activation. We did not observe any alterations on CD25 expression induced by BSO or NAC. However, our results demonstrated that NAC treatment induced an increase in CD69 expression on unstimulated CD8(+) T lymphocytes obtained from HTLV-1 infected individuals, healthy donors and HTLV carriers. Therefore, our results suggest that the cellular proliferation promoted by the infection with HTLV-1 and the activation phenotype of CD8(+) T lymphocytes can be regulated by changing the intracellular GSH levels; suggesting the modulation of these intracellular levels as a new approach for the treatment of pathologies associated with the HTLV-1 infection.
authors.affiliation: Lab. de Imunologia Básica e Aplicada, Depto. de Imunologia, Instituto de Microbiologia Paulo de Góes, Rio de Janeiro, Brazil.
authors.forename: Renata
authors.initials: R
authors.lastname: Novaes
authors.forename: Célio G
authors.initials: CG
authors.lastname: Freire-de-Lima
authors.forename: Raquel Cavalcanti
authors.initials: RC
authors.lastname: de Albuquerque
authors.forename: Ottilia R
authors.initials: OR
authors.lastname: Affonso-Mitidieri
authors.forename: Otávio
authors.initials: O
authors.lastname: Espindola
authors.forename: Marco Antonio
authors.initials: MA
authors.lastname: Lima
authors.forename: Maria José
authors.initials: MJ
authors.lastname: de Andrada Serpa
authors.forename: Juliana
authors.initials: J
authors.lastname: Echevarria-Lima
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism; D000328:Adult; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002353:Carrier State / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D005978:Glutathione / Q000378:metabolism*; D015490:HTLV-I Infections / Q000276:immunology*; D015368:Human T-lymphotropic virus 1 / Q000276:immunology*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000378:metabolism; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D055815:Young Adult
chemical_list: D000111:Acetylcysteine; D005978:Glutathione; D008717:Methionine Sulfoximine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C065566:buthionine sulfoximine ethyl ester; C421109:multidrug resistance-associated protein 1
keywords: ABCC1/MRP1; ATLL; BSO; CTL; GSH; Glutathione; HAM-TSP; HTLV-1; HTLV-1-associated myelopathy/tropical spastic paraparesis; INDO; Indomethacin; N-acetylcysteine; NAC; PBMC; ROS; Spontaneous lymphocyte proliferation; adult T-cell leukemia/lymphoma; cytotoxic T lymphocyte; dl-Buthionine-[S,R]-sulfoximine; glutathione; human T-cell lymphotropic virus type 1; multidrug resistance protein; peripheral blood mononuclear cells; reactive oxygen species