Antiretroviral agent (R)-9-(2-phosphonomethoxypropyl)adenine stimulates cytokine and nitric oxide production.
The immunomodulatory properties of (R)-enantiomer of 9-(2-phoshonomethoxypropyl)adenine ((R)-PMPA), one of the most potent acyclic nucleotide analogs effective against human immunodeficiency virus (HIV), were investigated under in vitro conditions using murine peritoneal macrophages. Remaining without influence on interferon-gamma and interleukin-2 expression, (R)-PMPA dramatically stimulated in a concentration- and time-dependent manner the secretion of tumor necrosis factor alpha (TNF-alpha) and interleukin-10. It also substantially augmented the production of nitric oxide (NO) induced by exogenous interferon-gamma. Inhibitory experiments using neutralizing antibodies against TNF-alpha and/or interleukin-10 demonstrated that these two cytokines are major factors responsible for triggering the underlying mechanism(s) leading to enhanced NO production. The novel findings on the immunomodulatory potential of acyclic nucleotide analogs are discussed in the context of their possible implication in antiviral therapeutic efficacy.
Zídek
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Institute of Pharmacology, Academy of Sciences of the Czech Republic, Prague. zidekz@biomed.cas.cz
Holý
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Franková
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D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002478:Cells, Cultured; D003470:Culture Media; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D007150:Immunohistochemistry; D007213:Indomethacin / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis*; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D013268:Stimulation, Chemical; D000068698:Tenofovir; D013806:Theophylline / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000276:Adjuvants, Immunologic; D019380:Anti-HIV Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003470:Culture Media; D016207:Cytokines; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D009569:Nitric Oxide; D007371:Interferon-gamma; D000068698:Tenofovir; D013806:Theophylline; D000225:Adenine; D007213:Indomethacin