Immunomodulatory properties of antiviral acyclic nucleotide analogues: cytokine stimulatory and nitric oxide costimulatory effects.
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.
Zídek
Z
Z
Institute of Pharmacology, Academy of Sciences of the Czech Republic, Prague.
Holý
A
A
Franková
D
D
D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis*; D009711:Nucleotides / Q000737:chemistry / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D000998:Antiviral Agents; D016207:Cytokines; D009711:Nucleotides; D009943:Organophosphorus Compounds; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D009569:Nitric Oxide; D007371:Interferon-gamma