Esophageal Epithelial-Derived IL-33 Is Upregulated in Patients with Heartburn.

Hiroo Sei,Takashi Kondo,Hirokazu Fukui,Tadayuki Oshima,Jiro Watari,Toshihiko Tomita,Takahisa Yamasaki,Hiroto Miwa,Jing Shan,Takuya Okugawa,Liping Wu,Ken-Ichi Mukaisho

doi:10.1371/journal.pone.0154234

Hiroo Sei, Takashi Kondo + Show 10 more

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https://doi.org/10.1371/journal.pone.0154234

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Abstract

BackgroundInterleukin-33 (IL-33) is a tissue-derived cytokine that is constitutively expressed in epithelial cells of tissues exposed to the environment and plays a role in sensing damage caused by inflammatory diseases. IL-33 acts as both a traditional cytokine and as a chromatin-associated nuclear factor in both innate and adaptive immunity. We recently showed that IL-33 in esophageal mucosa is upregulated in reflux esophagitis. However, IL-33 expression in patients with heartburn without mucosal injury and its relationship with intercellular space (ICS) have never been examined. We therefore examined the expression of cytokines and ICS in patients with heartburn.MethodsThe expression of IL-33 in the middle and distal esophageal mucosa of patients with heartburn without mucosal break and control samples was examined using real-time RT-PCR and immunofluorescence. The mRNA expression of IL-6, IL-8, MCP-1, and RANTES, and ICS was also analyzed.ResultsIL-33 expression and the mean ICS were significantly increased in the mucosa of patients with heartburn compared to that of the control. IL-33 and ICS were not different between the patients who were taking a PPI and those who were not. The upregulated IL-33 expression in the heartburn group was located in the nuclei of the basal cell layer. Although IL-6, IL-8, MCP-1 and RANTES levels were not different between control and patients with heartburn samples, IL-33 mRNA levels were still significantly correlated with IL-6, IL-8, or MCP-1 mRNA levels.ConclusionNuclear IL-33 is upregulated in patients with heartburn. Upregulated IL-33 in heartburn patients is related to the symptoms.

Highlights

Gastroesophageal reflux disease (GERD) is one of the most common gastrointestinal diseases and its incidence is increasing [1]
IL-6, IL-8, MCP1 and RANTES levels were not different between control and patients with heartburn samples, IL-33 messenger RNA (mRNA) levels were still significantly correlated with IL-6, IL-8, or monocyte chemotactic protein-1 (MCP-1) mRNA levels
Upregulated IL-33 in heartburn patients is related to the symptoms

Summary

Introduction

Gastroesophageal reflux disease (GERD) is one of the most common gastrointestinal diseases and its incidence is increasing [1]. Since esophageal inflammation occurs prior to macroscopic or even microscopic signs of mucosal injury in GERD, a new view has been proposed of the cause of this disease. In this new model it is suggested that gastroesophageal reflux (GER) causes esophagitis through a cytokine-mediated mechanism rather than through caustic acid-induced direct mucosal injury and that cytokines are upregulated in erosive esophagitis [4]. IL-33 expression in patients with heartburn without mucosal injury and its relationship with intercellular space (ICS) have never been examined. We examined the expression of cytokines and ICS in patients with heartburn

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Conclusion