Tenofovir selectively regulates production of inflammatory cytokines and shifts the IL-12/IL-10 balance in human primary cells.

Abstract

OBJECTIVES:

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: Jesper Melchjorsen, Michael W Risør, Ole S Søgaard, Kieran L O'Loughlin, Sue Chow, Søren R Paludan, Svend Ellermann-Eriksen, David W Hedley, Hans Minderman, Lars Østergaard, Martin Tolstrup
• Journal: Journal of acquired immune deficiency syndromes (1999) (J Acquir Immune Defic Syndr) Vol. 57 Issue 4 Pg. 265-75 (Aug 01 2011) ISSN: 1944-7884 [Electronic] United States
• PMID: 21471820 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-HIV Agents
• Chemokine CCL3
• Interleukin-8
• NF-kappa B
• Organophosphonates
• Toll-Like Receptors
• Tumor Necrosis Factor-alpha
• Interleukin-10
• Interleukin-12
• Zidovudine
• Tenofovir
• Mitogen-Activated Protein Kinases
• Adenine

Topics

• Adenine (analogs & derivatives, pharmacology)
• Anti-HIV Agents (pharmacology)
• Cell Line
• Chemokine CCL3 (drug effects, metabolism)
• Gene Expression Regulation (drug effects)
• Humans
• Interleukin-10 (genetics, metabolism)
• Interleukin-12 (genetics, metabolism)
• Interleukin-8 (drug effects, metabolism)
• Leukocytes, Mononuclear (drug effects, metabolism)
• Mitogen-Activated Protein Kinases (metabolism)
• Monocytes (drug effects, immunology)
• NF-kappa B (metabolism)
• Organophosphonates (pharmacology)
• Tenofovir
• Toll-Like Receptors (metabolism)
• Tumor Necrosis Factor-alpha (pharmacology)
• Zidovudine (pharmacology)