Lars Jørgen Østergaard

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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

OBJECTIVES:: In this study, we aimed to study the possible immune-modulatory effects of HIV NRTIs during secondary infections and inflammation, focusing on inflammatory cytokine responses and the IL-12/ IL-10 balance. METHODS:: We investigated the in vitro effect of tenofovir and zidovudine 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 TNF-α and the pathogens cytomegalovirus (CMV), Neisseria meningitides, Escherichia coli and Streptococcus pneumoniae. Cytokine levels were measured using ELISA and luminex technology. RNA levels were assessed using real-time PCR. Activity of MAPK and NF-κB signaling were evaluated using flow cytometry and multispectral imaging cytometry, respectively. RESULTS:: Tenofovir decreased and zidovudine increased both IL-8 and CCL3 production from monocytes after stimulation with TLR ligands, TNF-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. Zidovudine 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 (MAPK) and Nuclear Factor kappa B (NF-κB) pathways. CONCLUSION:: Our data suggest divergent effects of tenofovir and zidovudine 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 NRTI affects overall inflammation and early immune responses against secondary pathogens.
Original languageEnglish
JournalJ A I D S
Pages (from-to)265-275
Publication statusPublished - 5 Apr 2011

See relations at Aarhus University Citationformats

ID: 36843628