Macrophage activation by antiviral acyclic nucleoside phosphonates in dependence on priming immune stimuli

Abstract

Acyclic nucleoside phosphonates (ANPs) are potent broad-spectrum antivirals, also effective against immunodeficiency viruses and hepatitis viruses. Effects of several ANPs on in vitro cytokine gene expression and nitric oxide (NO) production by murine peritoneal macrophages were investigated. Included in the study were 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA; Adefovir), 9-(R)-[2-(phosphonomethoxy)propyl]adenine [(R)-PMPA; Tenofovir], 9-(S)-[2-(phosphonomethoxy)propyl]adenine; (S)-PMPA), 9-[2-(phosphonomethoxy)ethyl]-2,6-diaminopurine (PMEDAP), 9-(R)-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine (PMPDAP), and 9-[2-(phosphonomethoxy)ethyl]guanine (PMEG). Some of them, i.e. (R)-PMPA, (S)-PMPA, and PMEG, stimulate secretion of TNF-α and IL-10 in a concentration-dependent manner, and enhance the IFN-γ-induced secretion of TNF-α. Although unable to activate production of nitric oxide (NO) on their own, these compounds substantially augment NO formation induced by IFN-γ. Analysis of the expression of inducible NO synthase mRNA indicates that the NO-enhancing effect of ANPs is mediated posttranscriptionally. In contrast to IFN-γ, production of NO triggered by lipopolysaccharide (LPS) alone, or synergistically by LPS+IFN-γ, remains unaltered by ANPs. The immunomodulatory effects have been differentially expressed in distinct genotypes of inbred strains of mice, including the low NO-responders Balb/c and high NO-responders C3H/HeN. Although less effectively, PMEG and (R)-PMPA also increase production of TNF-α and NO by the IFN-γ- but not LPS-co-stimulated macrophages from C3H/HeJ mice, which are otherwise hypo-responsive to major immune stimuli provided by IFN-γ and LPS. It can be concluded that the expression of immunomodulatory properties of ANPs depends on the immune state of cells and its activation by distinct priming signals.