Interferon γ-Induced Nuclear Interleukin-33 Potentiates the Release of Esophageal Epithelial Derived Cytokines

• Published in: PloS one Vol. 11; no. 3; p. e0151701
• Main Authors: Shan, Jing, Oshima, Tadayuki, Wu, Liping, Fukui, Hirokazu, Watari, Jiro, Miwa, Hiroto
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17-03-2016; Public Library of Science (PLoS)
• Subjects: Acids; Biology and Life Sciences; Blotting, Western; Cell activation; Cell Nucleus - metabolism; Cells, Cultured; Colony-stimulating factor; Cytokines; Cytokines - metabolism; Cytokines - physiology; Enzyme-linked immunosorbent assay; Epithelial cells; Epithelium - drug effects; Epithelium - metabolism; Epithelium - physiology; Esophagitis - metabolism; Esophagitis - physiopathology; Esophagus; Esophagus - drug effects; Esophagus - metabolism; Esophagus - physiology; Fluorescent Antibody Technique; Gastroenterology; Gastroesophageal reflux; Gastroesophageal Reflux - metabolism; Gastroesophageal Reflux - physiopathology; Granulocyte-macrophage colony-stimulating factor; Humans; Immunoassay; Immunofluorescence; In vitro methods and tests; Inflammation; Interferon; Interferon-gamma - pharmacology; Interleukin 6; Interleukin 8; Interleukin-33 - analysis; Interleukin-33 - physiology; Interleukin-6 - metabolism; Interleukin-6 - physiology; Interleukin-8 - metabolism; Interleukin-8 - physiology; Internal medicine; Janus kinase; Kinases; Laboratories; Lymphocytes T; Macrophages; MAP kinase; Medical research; Medicine; Medicine and Health Sciences; Monocyte chemoattractant protein; Monocyte chemoattractant protein 1; Mucosa; Multiplexing; Nuclei; Nuclei (cytology); Pathogenesis; Pharmacology; Physiology; Polymerase chain reaction; Protein kinase; Proteins; Research and Analysis Methods; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleic acid; RNA; Signal transduction; Signal Transduction - drug effects; Signal Transduction - physiology; Signaling; Studies; Transcription factors; Transducers; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-TNF; Tyrosine; Wound healing; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0151701

Esophageal epithelial cells are an initiating cell type in esophageal inflammation, playing an essential role in the pathogenesis of gastroesophageal reflux disease (GERD). A new tissue-derived cytokine, interleukin-33 (IL-33), has been shown to be upregulated in esophageal epithelial cell nuclei in GERD, taking part in mucosal inflammation. Here, inflammatory cytokines secreted by esophageal epithelial cells, and their regulation by IL-33, were investigated.
In an in vitro stratified squamous epithelial model, IL-33 expression was examined using quantitative RT-PCR, western blot, ELISA, and immunofluorescence. Epithelial cell secreted inflammatory cytokines were examined using multiplex flow immunoassay. IL-33 was knocked down with small interfering RNA (siRNA) in normal human esophageal epithelial cells (HEECs). Pharmacological inhibitors and signal transducers and activators of transcription 1 (STAT1) siRNA were used to explore the signaling pathways.
Interferon (IFN)γ treatment upregulated nuclear IL-33 in HEECs. Furthermore, HEECs can produce various inflammatory cytokines, such as IL-6, IL-8, monocyte chemoattractant protein 1 (MCP-1), regulated on activation normal T-cell expressed and presumably secreted (RANTES), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in response to IFNγ. Nuclear, but not exogenous IL-33, amplified IFN induction of these cytokines. P38 mitogen-activated protein kinase (MAPK) and janus protein tyrosine kinases (JAK)/STAT1 were the common signaling pathways of IFNγ-mediated induction of IL-33 and other cytokines.
Esophageal epithelial cells can actively participate in GERD pathogenesis through the production of various cytokines, and epithelial-derived IL-33 might play a central role in the production of these cytokines.