A novel immunomodulatory mechanism of ribavirin in suppressing natural killer cell function

• Published in: Biochemical pharmacology 2010-01, Vol.79 (2), p.188-197
• Main Authors: Ogbomo, Henry, Michaelis, Martin, Altenbrandt, Behric, Doerr, Hans Wilhelm, Cinatl, Jindrich
• Format: Article
• Language: English
• Subjects: Antiviral agents; Antiviral Agents - pharmacology; Biological and medical sciences; Blotting, Western; c-Jun amino-terminal kinase; Cytotoxicity; Degranulation; Enzyme-Linked Immunosorbent Assay; Extracellular signal-regulated kinase; Flow cytometry; g-Interferon; Humans; IL-15 receptors; Immunologic Factors - pharmacology; Immunomodulation; Interleukin 15 receptors; Janus kinase; K562 Cells; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Medical sciences; Natural killer cells; NK cell activating receptors; NK cell degranulation; NK cell signaling; NKG2 antigen; Perforin and granzyme B release; Pharmacology. Drug treatments; Receptor mechanisms; Ribavirin; Ribavirin - pharmacology; Signal Transduction; Stat1 protein; Stat3 protein; Stat5 protein; Transcription; Western blotting
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2009.07.026

Ribavirin, a broad-spectrum anti-viral drug, exhibits immunomodulatory activities. To study direct effects of ribavirin on natural killer (NK) cell effector functions and signaling, resting NK cells and interleukin (IL)-15-activated NK cells were treated for 5 days with therapeutic ribavirin concentrations ranging from 5μg/ml to 20μg/ml. Both resting and IL-15-activated NK cells that were not treated with ribavirin were used as control. Cytotoxicity assays, flow cytometry, enzyme linked immunosorbent assays, and Western blot experiments were performed to elucidate ribavirin effect on NK cells. Results showed that ribavirin (not toxic at concentrations tested; IC50>80μg/ml) had no influence on lysis of target cells by freshly isolated NK cells. Conversely, ribavirin dose-dependently inhibited lysis of target cells by up to 66% and impaired interferon gamma production when IL-15-activated NK cells were used. IL-15-induced increased expression and hence function of NK cell activating receptors including NKp30, NKp44, NKp46 and NKG2D were selectively down-regulated and impaired. These inhibitory effects were associated with the down-regulation of IL-15 receptor beta and gamma expression. Accordingly, downstream events involved in NK cell signaling via IL-15 receptors including the activation of Janus kinase (Jak)-1, signal transducer and activator of transcription STAT-1, STAT-3, and STAT-5 as well as pathways responsible for NK cell degranulation including extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) were impaired. These results reveal a novel mechanism by which ribavirin exerts its immunomodulatory activities.