title: IL-1β is a key cytokine that induces trypsin upregulation in the influenza virus-cytokine-trypsin cycle.
abstract: Severe influenza is characterized by a cytokine storm, and the influenza virus-cytokine-trypsin cycle is one of the important mechanisms of viral multiplication and multiple organ failure. The aim of this study was to define the key cytokine(s) responsible for trypsin upregulation. Mice were infected with influenza virus strain A/Puerto Rico/8/34 (H1N1) or treated individually or with a combination of interleukin-1β, interleukin-6, and tumor necrosis factor α. The levels of these cytokines and trypsin in the lungs were monitored. The neutralizing effects of anti-IL-1β antibodies on cytokine and trypsin expression in human A549 cells and lung inflammation in the infected mice were examined. Infection induced interleukin-1β, interleukin-6, tumor necrosis factor α, and ectopic trypsin in mouse lungs in a dose- and time-dependent manner. Intraperitoneal administration of interleukin-1β combined with other cytokines tended to upregulate trypsin and cytokine expression in the lungs, but the combination without interleukin-1β did not induce trypsin. In contrast, incubation of A549 cells with interleukin-1β alone induced both cytokines and trypsin, and anti-interleukin-1β antibody treatment abrogated these effects. Administration of the antibody in the infected mice reduced lung inflammation area. These findings suggest that IL-1β plays a key role in trypsin upregulation and has a pathological role in multiple organ failure.
authors.affiliation: Division of Enzyme Chemistry, Institute for Enzyme Research, Tokushima University, Tokushima, 770-8503, Japan.
authors.forename: I L
authors.initials: IL
authors.lastname: Indalao
authors.affiliation: Division of Enzyme Chemistry, Institute for Enzyme Research, Tokushima University, Tokushima, 770-8503, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sawabuchi
authors.affiliation: Division of Enzyme Chemistry, Institute for Enzyme Research, Tokushima University, Tokushima, 770-8503, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Takahashi
authors.affiliation: Division of Enzyme Chemistry, Institute for Enzyme Research, Tokushima University, Tokushima, 770-8503, Japan. kido@tokushima-u.ac.jp.
authors.forename: H
authors.initials: H
authors.lastname: Kido
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000276:immunology / Q000821:virology; D005260:Female; D054884:Host-Pathogen Interactions; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008810:Mice, Inbred C57BL; D009975:Orthomyxoviridae / Q000502:physiology*; D009976:Orthomyxoviridae Infections / Q000473:pathology*; D014357:Trypsin / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D014357:Trypsin