Differential effects of acyclic nucleoside phosphonates on nitric oxide and cytokines in rat hepatocytes and macrophages

• Published in: International immunopharmacology 2012-02, Vol.12 (2), p.342-349
• Main Authors: Kostecká, Petra, Holý, Antonín, Farghali, Hassan, Zídek, Zdeněk, Kmoníčková, Eva
• Format: Article
• Language: English
• Subjects: Acyclic nucleoside phosphonates; Animals; Biological and medical sciences; Cytokines; Cytokines - immunology; Cytokines - metabolism; Hepatitis B virus; Hepatocytes - drug effects; Hepatocytes - immunology; Hepatocytes - metabolism; Human immunodeficiency virus; Lipopolysaccharides - immunology; Lipopolysaccharides - pharmacology; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Male; Medical sciences; Nitric oxide; Nitric Oxide - immunology; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - immunology; Nitric Oxide Synthase Type II - metabolism; Nucleotides, Cyclic - immunology; Nucleotides, Cyclic - pharmacology; Organophosphonates - immunology; Organophosphonates - pharmacology; Pharmacology. Drug treatments; Rat hepatocytes; Rats; Rats, Wistar
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2011.12.005

Acyclic nucleoside phosphonates (ANP) are virostatics effective against viruses like hepatitis B virus and human immunodeficiency virus. Our previous reports indicated immunomodulatory activities of ANP in mouse and human innate immune cells. Recently, evidence has increased that hepatocytes may play an active role in immune regulation of the liver homeostasis or injury. In this study we investigated possible immunomodulatory effects of ANP on rat hepatocytes and macrophages. Nitric oxide (NO) production and secretion of cytokines (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-13, IL-18, IFN-γ, TNF-α and GM-CSF) were analyzed under in vitro conditions. Test compounds included: 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA; adefovir); 9-[2-(phosphonomethoxy)ethyl]-2,6-diaminopurine (PMEDAP); (R)- and (S)-enantiomers of 9-[2-(phosphonomethoxy)propyl]adenine [(R)-PMPA; tenofovir] and [(S)-PMPA]; 9-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine [(R)-PMPDAP] and [(S)-PMPDAP]. The group of test compounds also included their N6-substituted derivatives. Some of ANP which are able to induce NO production and cytokine secretion in cultured macrophages possess the same immunobiological activity in isolated hepatocytes. The extent of responses is in range of LPS/IFN-γ stimulation in both types of cells. The effects of active ANP on NO expression and cytokine secretion are dose- and time-dependent. Interestingly, the spectrum of detected cytokines induced by ANP is broader in hepatocytes. The results also confirm immunomodulatory effects of some ANP on rodent macrophages. Moreover, we demonstrate for the first time immunobiological reactivity of primary rat hepatocytes induced by exogenous ANP compounds. The potential of hepatocytes to synthesize cytokines can contribute to better understanding of liver immune function and can serve for pharmacological intervention in liver diseases. ► Acyclic nucleoside phosphonates (ANP) are used as antivirals. ► Immunomodulatory potential of ANP was examined. ► ANP induce NO production and cytokines secretion in rat macrophages. ► ANP stimulate NO and cytokine secretion in rat hepatocytes. ► Synthetic ANP can be used as a model of immunoreactivity in hepatocytes.