Antiretroviral agent (R)-9-(2-phosphonomethoxypropyl)adenine stimulates cytokine and nitric oxide production

Abstract

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- γ and interleukin-2 expression, (R)-PMPA dramatically stimulated in a concentration- and time-dependent manner the secretion of tumor necrosis factor alpha (TNF- α) and interleukin-10. It also substantially augmented the production of nitric oxide (NO) induced by exogenous interferon- γ. Inhibitory experiments using neutralizing antibodies against TNF- α 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.