title: Key role of regulated upon activation normal T-cell expressed and secreted, nonstructural protein1 and myeloperoxidase in cytokine storm induced by influenza virus PR-8 (A/H1N1) infection in A549 bronchial epithelial cells.
abstract: Influenza virus infection causes severe respiratory disease such as that due to avian influenza (H5N1). Influenza A viruses proliferate in human epithelial cells, which produce inflammatory cytokines/chemokines as a "cytokine storm" attenuated with the viral nonstructural protein 1 (NS1). Cytokine/chemokine production in A549 epithelial cells infected with influenza A/H1N1 virus (PR-8) or nonstructural protein 1 (NS1) plasmid was examined in vitro. Because tumor necrosis factor-α (TNF-α) and regulated upon activation normal T-cell expressed and secreted (RANTES) are predominantly produced from cells infected with PR-8 virus, the effects of mRNA knockdown of these cytokines were investigated. Small interfering (si)TNF-α down-regulated RANTES expression and secretion of RANTES, interleukin (IL)-8, and monocyte chemotactic protein-1 (MCP-1). In addition, siRANTES suppressed interferon (IFN)-γ expression and secretion of RANTES, IL-8, and MCP-1, suggesting that TNF-α stimulates production of RANTES, IL-8, MCP-1, and IFN-γ, and RANTES also increased IL-8, MCP-1, and IFN-γ. Furthermore, administration of TNF-α promoted increased secretion of RANTES, IL-8, and MCP-1. Administration of RANTES enhanced IL-6, IL-8, and MCP-1 production without PR-8 infection. These results strongly suggest that, as an initial step, TNF-α regulates RANTES production, followed by increase of IL-6, IL-8, and MCP-1 and IFNs concentrations. At a later stage, cells transfected with viral NS1 plasmid showed production of a large amount of IL-8 and MCP-1 in the presence of the H(2)O(2)-myeloperoxidse (MPO) system, suggesting that NS1 of PR-8 may induce a "cytokine storm" from epithelial cells in the presence of an H(2)O(2)-MPO system.
authors: Inflammation Program, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, Japan.
authors: Thuy Thi Bich
authors: TT
authors: Phung
authors: Ryuichi
authors: R
authors: Sugamata
authors: Kazuko
authors: K
authors: Uno
authors: Yasuaki
authors: Y
authors: Aratani
authors: Keiko
authors: K
authors: Ozato
authors: Shoji
authors: S
authors: Kawachi
authors: Liem
authors: L
authors: Thanh Nguyen
authors: Toshinori
authors: T
authors: Nakayama
authors: Kazuo
authors: K
authors: Suzuki
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018946:Chemokine CCL5 / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D018925:Chemokines / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D016207:Cytokines / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D015536:Down-Regulation; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology* / Q000502:physiology; D007251:Influenza, Human / Q000276:immunology* / Q000821:virology; D008213:Lymphocyte Activation; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology / Q000821:virology; D009195:Peroxidase / Q000008:administration & dosage / Q000378:metabolism*; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000235:genetics; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018946:Chemokine CCL5; D018925:Chemokines; D016207:Cytokines; C085820:INS1 protein, influenza virus; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D017361:Viral Nonstructural Proteins; D006861:Hydrogen Peroxide; D009195:Peroxidase