Abstract
BackgroundEsophageal 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.MethodsIn 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.ResultsInterferon (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.ConclusionsEsophageal 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.
Highlights
The esophageal epithelium was thought to be a tissue that forms a barrier against caustic chemical injury, remaining quiescent until activated by an invading army of immune effector cells
Esophageal epithelial cells can actively participate in gastroesophageal reflux disease (GERD) pathogenesis through the production of various cytokines, and epithelial-derived IL-33 might play a central role in the production of these cytokines
Reverse Transcription (RT)-qPCR revealed that IFNγ, but not TNF-α, significantly increased IL-33 mRNA compared with untreated cells in a time- and dose-dependent manner
Summary
The esophageal epithelium was thought to be a tissue that forms a barrier against caustic chemical injury, remaining quiescent until activated by an invading army of immune effector cells This concept has been challenged by studies showing that esophageal epithelial cells can produce various inflammatory cytokines, such as interleukin (IL)-8 and IL6, in response to intraluminal stimuli including acid, bile acid, and trypsin [1,2,3,4,5,6]. Interferon gamma (IFNγ), tumor necrosis factor alpha (TNF-α), IL-1β, IL10, monocyte chemoattractant protein 1 (MCP-1), and regulated on activation normal T-cell expressed and presumably secreted (RANTES) have been found to be upregulated in mucosal biopsy specimens [1, 8, 9] Whether these inflammatory cytokines can be secreted by esophageal epithelial cells and how they are regulated remains unclear. Inflammatory cytokines secreted by esophageal epithelial cells, and their regulation by IL33, were investigated
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