Glycyrrhizin inhibits highly pathogenic H5N1 influenza A virus-induced pro-inflammatory cytokine and chemokine expression in human macrophages

Abstract

Hypercytokinaemia is thought to contribute to highly pathogenic H5N1 influenza A virus disease. Glycyrrhizin is known to exert immunomodulatory and anti-inflammatory effects and therefore a candidate drug for the control of H5N1-induced pro-inflammatory gene expression. Here, the effects of an approved parenteral glycyrrhizin preparation were investigated on H5N1 virus replication, H5N1-induced pro-inflammatory responses, and H5N1-induced apoptosis in human monocyte-derived macrophages. Glycyrrhizin 100 μg/ml, a therapeutically achievable concentration, impaired H5N1-induced production of CXCL10, interleukin 6, and CCL5 and inhibited H5N1-induced apoptosis but did not interfere with H5N1 replication. Global inhibition of immune responses may result in the loss of control of virus replication by cytotoxic immune cells including natural killer cells and cytotoxic CD8(+) T-lymphocytes. Notably, glycyrrhizin concentrations that inhibited H5N1-induced pro-inflammatory gene expression did not affect cytolytic activity of natural killer cells. Since H5N1-induced hypercytokinaemia is considered to play an important role within H5N1 pathogenesis, glycyrrhizin may complement the arsenal of potential drugs for the treatment of H5N1 disease.

Differences in highly pathogenic avian influenza viral pathogenesis and associated early inflammatory response in chickens and ducks

“…This could mean that the high but delayed pro-inflammatory cytokine (IL-1b and IL-6) and IFN-g response was too late to clear the virus infection in chickens. In other studies it was shown that high expression of IL-6 (Michaelis et al, 2010;Hayashi et al, 2011) and IFN-a, IFN-b, IL-15, and IL-18 mRNA in the lung of HPAI H5N1-infected chickens was accompanied by high levels of viral titres (median egg infectious dose) (Suzuki et al, 2009 Karpala et al (2011a), the highly elevated IFN-g response in the lung of HPAI-infected chickens after 1.5 d.p.i. is an indication of an active Th1 immune response.…”

Therapy of experimental influenza virus infection with pyrrolidine dithiocarbamate

“…This observation was confirmed by the reduction in the IFN-c expression. In general, IAV replicates in epithelial cells [26] as well as in immune cells like macrophages [52,53], which results in the release of numerous potent immune mediators. For example, IFN-a/b and IL-18 were secreted from IAV-infected macrophages and caused thereby an activation of natural killer (NK) cells and T-lymphocytes, which leads to IFN-c release [54].…”

Medicinal Herbs and Plant Extracts for Influenza: Bioactivity, Mechanism of Anti-influenza Effects, and Modulation of Immune Responses

“…Cytokines are produced locally and systemically in animals during influenza infection [87][88][89], and the occurrence of the cytokine storm "hypercytokinemia" has been proposed to contribute to the increased severity of diseases caused by the highly pathogenic viruses [90][91][92]. In addition, antagonism of TNF-a, IL-1a, and IL-6 has been found to partly prevent the decrease in feeding and loss of body weight of mice induced by influenza virus infection [93].…”

“…The protective mechanism was therefore suggested to be the induction of IFN-g in T cells [57]. In a more recent study, the immune responses induced by glycyrrhizin may result in the loss of control of viral replication by cytotoxic immune cells, including NK cells and CD8 þ T lymphocytes [92].…”

“…More recently, isolated alkylamides from E. purpurea suppressed the production of TNF-a and PGE2 from infected cells and also strongly inhibited the production of granulocyte colony-stimulating factor, chemokine (C-C motif) ligand 2 (CCL2)/MCP-1, CCL3/macrophage inflammatory protein-1a, and CCL5/RANTES [98]. In addition, glycyrrhizin, which is the active component of licorice roots, has been found to impair H5N1-induced production of C-X-C motif chemokine 10 , IL-6, and CCL5 and inhibits H5N1-induced apoptosis in human monocyte-derived macrophages [92].…”