Tohoku J. Exp. Med., 2018 May, 245(1)

Leptin Aggravates Reflux Esophagitis by Increasing Tissue Levels of Macrophage Migration Inhibitory Factor in Rats

TSUGIHIRO MURATA,1 KIYOTAKA ASANUMA,1 NOBUYUKI ARA,1 KATSUNORI IIJIMA,2 WAKU HATTA,1 SHIN HAMADA,1 NAOKI ASANO,1 TOMOYUKI KOIKE,1 AKIRA IMATANI,1 ATSUSHI MASAMUNE1 and TOORU SHIMOSEGAWA1

1Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
2Department of Gastroenterology and Neurology, Akita University Graduate School of Medicine, Akita, Akita, Japan

Leptin, produced primarily by the adipose tissue, acts as a pro-inflammatory modulator, thereby contributing to the development of obesity-related disease. Although high levels of leptin in the obese are closely related to gastroesophageal reflux disease, the mechanism by which leptin influences esophageal inflammation remains unknown. Macrophage migration inhibitory factor (MIF) is produced by immune cells, such as T lymphocytes and macrophages, and MIF is known to induce the production of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and interleukin 6 (IL-6). We therefore investigated the mechanism whereby leptin aggravates reflux esophagitis, by focusing on esophageal tissue levels of MIF and CD3+ T lymphocytes, both of which are crucial for the reflux-induced epithelial damage. Esophageal inflammation was surgically induced in male Wistar rats by ligating the forestomach and narrowing the duodenum to facilitate gastroesophageal reflux, followed by administration of leptin or vehicle with an osmotic pump system for 1 week. We demonstrated that the administration of leptin exacerbated the reflux esophagitis with the apparent infiltration of CD3+ T lymphocytes and caused the significant increase in the esophageal tissue levels of MIF. Moreover, the leptin caused increases in the esophageal tissue levels of TNF-α, IL-1β and IL-6, downstream targets of MIF. Importantly, the increases in these pro-inflammatory cytokines were accompanied by increased protein levels of phospho-STAT3 and phospho-AKT, pivotal molecules of leptin signaling pathways. In conclusion, through enhancing the MIF-induced inflammatory signaling, leptin could contribute to the development of gastroesophageal reflux disease.

Key words —— CD3+ T lymphocytes; leptin; macrophage migration inhibitory factor; obesity; reflux esophagitis

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Tohoku J. Exp. Med., 2018, 245, 45-53

Correspondence: Kiyotaka Asanuma, Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.

e-mail: takaxeve2004@aurora.ocn.ne.jp