title: Tenofovir selectively regulates production of inflammatory cytokines and shifts the IL-12/IL-10 balance in human primary cells.
abstract: OBJECTIVE
  In this study, we aimed to investigate the possible immune modulatory effects of HIV nucleoside reverse transcriptase inhibitors during secondary infections and inflammation, focusing on inflammatory cytokine responses and the interleukin (IL)-12/IL-10 balance.
  
  
  METHODS
  We investigated the in vitro effect of tenofovir and zidovudine (AZT) on production of proinflammatory cytokines in monocytes and human peripheral blood mononuclear cells (PBMCs). Stimulation panels included Toll-Like receptor (TLR) ligands; the inflammation mediator tumor necrosis factor-α; and the pathogens cytomegalovirus, Neisseria meningitides, Escherichia coli, and Streptococcus pneumoniae. Cytokine levels were measured using enzyme-linked immunosorbent assay and luminex technology. RNA levels were assessed using real-time polymerase chain reaction. Activity of mitogen-activated protein kinase and NF-κB signaling was evaluated using flow cytometry and multispectral imaging cytometry, respectively.
  
  
  RESULTS
  Tenofovir decreased and AZT increased both IL-8 and CCL3 production from monocytes after stimulation with TLR ligands, tumor necrosis factor-α, or live pathogens. Similarly, tenofovir decreased CCL3 levels in human PBMCs. Furthermore, tenofovir strongly decreased induction of IL-10 but increased levels of IL-12. AZT did not affect IL-12 or IL-10 levels. The observed drug-induced changes in cytokine production were independent from transcriptional regulation through the mitogen-activated protein kinase and nuclear factor kappa B pathways.
  
  
  CONCLUSIONS
  Our data suggest divergent effects of tenofovir and AZT on proinflammatory responses in monocytes (CCL3 and IL-8) and PBMCs (CCL3). Moreover, tenofovir shifts the IL-10/IL-12 balance after cell stimulation with TLR ligands or infection with live bacteria, thus suggesting that the choice of nucleoside reverse transcriptase inhibitor affects overall inflammation and early immune responses against secondary pathogens.
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark. jespmelc@rm.dk
authors.forename: Jesper
authors.initials: J
authors.lastname: Melchjorsen
authors.forename: Michael W
authors.initials: MW
authors.lastname: Risør
authors.forename: Ole S
authors.initials: OS
authors.lastname: Søgaard
authors.forename: Kieran L
authors.initials: KL
authors.lastname: O'Loughlin
authors.forename: Sue
authors.initials: S
authors.lastname: Chow
authors.forename: Søren R
authors.initials: SR
authors.lastname: Paludan
authors.forename: Svend
authors.initials: S
authors.lastname: Ellermann-Eriksen
authors.forename: David W
authors.initials: DW
authors.lastname: Hedley
authors.forename: Hans
authors.initials: H
authors.lastname: Minderman
authors.forename: Lars
authors.initials: L
authors.lastname: Østergaard
authors.forename: Martin
authors.initials: M
authors.lastname: Tolstrup
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D054405:Chemokine CCL3 / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism*; D016209:Interleukin-8 / Q000187:drug effects / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D063065:Organophosphonates / Q000494:pharmacology*; D000068698:Tenofovir; D051193:Toll-Like Receptors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D054405:Chemokine CCL3; D016209:Interleukin-8; D016328:NF-kappa B; D063065:Organophosphonates; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D015215:Zidovudine; D000068698:Tenofovir; D020928:Mitogen-Activated Protein Kinases; D000225:Adenine