Saquinavir‐NO Inhibits IL‐6 Production in Macrophages

• Published in: Basic & clinical pharmacology & toxicology 2014-12, Vol.115 (6), p.499-506
• Main Authors: Momčilović, Miljana, Mangano, Katia, Jevtić, Bojan, Mammana, Santa, Stošić‐Grujičić, Stanislava, Nicoletti, Ferdinando, Miljković, Djordje
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cells, Cultured; Drug therapy; Immune system; Interleukin-10 - antagonists & inhibitors; Interleukin-10 - biosynthesis; Interleukin-1beta - biosynthesis; Interleukin-6 - antagonists & inhibitors; Interleukin-6 - biosynthesis; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - metabolism; Medical research; Medical sciences; Mice, Inbred C57BL; Pharmacology. Drug treatments; Rats; Saquinavir - analogs & derivatives; Saquinavir - pharmacology; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 1742-7835; 1742-7843
• DOI: 10.1111/bcpt.12268

Covalent attachment of the nitric oxide (NO) moiety to the HIV protease inhibitor Saquinavir (Saq) produced a new chemical entity, named Saquinavir‐NO, (Saq‐NO) with reduced toxicity and potent immunoregulatory influence on T lymphocytes. In this study, we have compared head‐to‐head the effects of Saq‐NO and Saq on mouse and rat peritoneal macrophage cytokine secretion and NO production upon in vitro, ex vivo and in vivo conditions. The results demonstrate that Saq‐NO, but not Saq, potently decreased interleukin (IL)‐10, IL‐6 and nitrite accumulation and increased the levels of IL‐1β and tumour necrosis factor (TNF) in supernatants of mouse and rat macrophage cultures in vitro. Treatment of mice with Saq‐NO, but not Saq, inhibited ex vivo secretion of IL‐6 from macrophages. Consistent with these findings, Saq‐NO also reduced blood levels of IL‐6 in lipopolysaccharide‐treated mice. The observed inhibitory influence of Saq‐NO on IL‐6 generation in macrophages may be involved in the observed antitumour and immunomodulatory effects of the drug.