Acyclic nucleotide analogues exhibit strong activity against a broad range of viruses, including HIV-1 and -2. We have investigated their effects on in vitro secretion of cytokines and production of nitric oxide (NO) by murine peritoneal macrophages, factors known to play a role in virus replication. Included in the study were the most prominent compounds of the series: 9-(2-phosphonomethoxyethyl)adenine, 9-(2-phosphonomethoxyethyl)-2,6-diaminopurine, the (R)- and (S)-enantiomers of 9-(2-phosphonomethoxypropyl) adenine [(R)- or (S)-PMPA], (R)- and (S)-enantiomers of 9-(2-phosphonomethoxypropyl)-2,6-diaminopurine [(R)- or (S)-PMPDAP], 9-(2-phosphonomethoxyethyl)guanine (PMEG), and (S)-enantiomer of 1-(3-hydroxy-2-phosphonomethoxypropyl)cytosine [(S)-HPMPC]. PMEG, (R)-PMPA, and (S)-PMPA greatly enhanced the secretion of both tumour necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10), (R)-PMPDAP stimulated only TNF-alpha, other test compounds were ineffective. None of them influenced the secretion of IL-2 or interferon-gamma (IFN-gamma). Both TNF-alpha and IL-10 have been found to be major factors determining enhancing effects of PMEG, (R)-PMPA, and (S)-PMPA on production of NO generated by exogenous IFN-gamma. The study points to a possible implication of immunomodulatory properties in the antiviral effects of some acyclic nucleotide analogues. In addition, our data support the view that endogenous IL-10 can stimulate certain macrophage functions.

Institute of Pharmacology Academy of Sciences of the Czech Republic Prague

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Activation by 9-(R)-[2-(phosphonomethoxy)propyl]adenine of chemokine (RANTES, macrophage inflammatory protein 1alpha) and cytokine (tumor necrosis factor alpha, interleukin-10 [IL-10], IL-1beta) production