title: Effects of tenofovir on cytokines and nucleotidases in HIV-1 target cells and the mucosal tissue environment in the female reproductive tract.
abstract: Tenofovir (TFV) is a reverse transcriptase inhibitor used in microbicide preexposure prophylaxis trials to prevent HIV infection. Recognizing that changes in cytokine/chemokine secretion and nucleotidase biological activity can influence female reproductive tract (FRT) immune protection against HIV infection, we tested the hypothesis that TFV regulates immune protection in the FRT. Epithelial cells, fibroblasts, CD4(+) T cells, and CD14(+) cells were isolated from the endometrium (Em), endocervix (Cx), and ectocervix (Ecx) following hysterectomy. The levels of proinflammatory cytokines (macrophage inflammatory protein 3α [MIP-3α], interleukin 8 [IL-8], and tumor necrosis factor alpha [TNF-α]), the expression levels of specific nucleotidases, and nucleotidase biological activities were analyzed in the presence or absence of TFV. TFV influenced mRNA and/or protein cytokines and nucleotidases in a cell- and site-specific manner. TFV significantly enhanced IL-8 and TNF-α secretion by epithelial cells from the Em and Ecx but not from the Cx. In contrast, in response to TFV, IL-8 secretion was significantly decreased in Em and Cx fibroblasts but increased with fibroblasts from the Ecx. When incubated with CD4(+) T cells from the FRT, TFV increased IL-8 (Em and Ecx) and TNF-α (Cx and Ecx) secretion levels. Moreover, when incubated with Em CD14(+) cells, TFV significantly increased MIP-3α, IL-8, and TNF-α secretion levels relative to those of the controls. In contrast, nucleotidase biological activities were significantly decreased by TFV in epithelial (Cx) and CD4(+) T cells (Em) but increased in fibroblasts (Em). Our findings indicate that TFV modulates proinflammatory cytokines, nucleotidase gene expression, and nucleotidase biological activity in epithelial cells, fibroblasts, CD4(+) T cells, and CD14(+) cells at distinct sites within the FRT.
authors.affiliation: Department of Physiology and Neurobiology, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA nabanita.biswas@gmail.com charles.r.wira@dartmouth.edu.
authors.forename: Nabanita
authors.initials: N
authors.lastname: Biswas
authors.affiliation: Department of Physiology and Neurobiology, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Rodriguez-Garcia
authors.affiliation: Department of Physiology and Neurobiology, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Department of Physiology and Neurobiology, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Crist
authors.affiliation: Department of Physiology and Neurobiology, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
authors.forename: Jack E
authors.initials: JE
authors.lastname: Bodwell
authors.affiliation: Department of Physiology and Neurobiology, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
authors.forename: John V
authors.initials: JV
authors.lastname: Fahey
authors.affiliation: Department of Physiology and Neurobiology, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA nabanita.biswas@gmail.com charles.r.wira@dartmouth.edu.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Wira
mesh_terms: D015720:5'-Nucleotidase / Q000096:biosynthesis* / Q000235:genetics; D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002584:Cervix Uteri / Q000166:cytology / Q000187:drug effects; D054418:Chemokine CCL20 / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis*; D004717:Endometrium / Q000166:cytology / Q000187:drug effects; D004847:Epithelial Cells / Q000276:immunology; D005260:Female; D005347:Fibroblasts / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008875:Middle Aged; D009092:Mucous Membrane / Q000166:cytology / Q000187:drug effects; D063065:Organophosphonates / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D000068698:Tenofovir; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; C108355:CCL20 protein, human; C508606:CXCL8 protein, human; D054418:Chemokine CCL20; D016207:Cytokines; D016209:Interleukin-8; D018950:Lipopolysaccharide Receptors; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000068698:Tenofovir; D015720:5'-Nucleotidase; D000225:Adenine