Oncotarget

Research Papers:

Modulation of inflammation by toll-like receptor 4/nuclear factor-kappa B in diarrhea-predominant irritable bowel syndrome

Xing He, Li-Hong Cui _, Xiao-Hui Wang, Zhi-Hui Yan, Chao Li, San-Dong Gong, Yan Zheng, Zhe Luo and Ying Wang

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Oncotarget. 2017; 8:113957-113965. https://doi.org/10.18632/oncotarget.23045

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Abstract

Xing He1, Li-Hong Cui2, Xiao-Hui Wang2, Zhi-Hui Yan2, Chao Li2, San-Dong Gong2, Yan Zheng2, Zhe Luo2 and Ying Wang2

1Third Military Medical University, Chongqing 400038, China

2Department of Gastroenterology, Navy General Hospital of PLA, Beijing 100048, China

Correspondence to:

Li-Hong Cui, email: luckycui861@sina.com

Keywords: toll-like receptor 4; nuclear factor-kappa B; diarrhea-predominant irritable bowel syndrome; inflammatory cytokines; pyrrolidine dithiocarbamate

Received: August 12, 2017    Accepted: November 16, 2017    Published: December 08, 2017

ABSTRACT

In order to investigate the function of toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-κB) signal pathways in the pathogenesis of diarrhea-predominant irritable bowel syndrome (IBS-D), IBS-D animal models were established in wistar rats challenged with acute and chronic stresses (29 days). Wistar rats without stress-challenged were used as controls. IBS-D models were randomly divided into two groups: one was treated with normal saline, another group was treated with TLR4/NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC) (50mg/kg/week) for continuous four times. Our results demonstrate that continuous stresses can induce the characteristic symptoms of IBS-D, including high wet stool rate and intestinal flora imbalance. Further examinations of colon tissues show that the protein expression levels of TLR4 and NF-κB in IBS-D groups are higher than that in control group. The secretory levels of interleukin (IL-8), tumor necrosis factor α (TNFα), and myeloid differentiation factor 88 (MyD88) are significantly increased in IBS-D group. Administration with PDTC effectively downregulates levels of these inflammatory factors. In contrast, interleukin-10 (IL-10) is in an opposite alteration with lower levels in IBS-D groups and the PDTC treatment increases it to the levels as in control group. Moreover, inhibition of the TLR4/NF-κB by PDTC improves the microstructure of intestinal mucosa mainly by increasing the height of villi. Our results suggest that TLR4/NF-κB signal pathway plays an important role in the modulation of inflammatory responses in IBS-D, which might be a therapeutic target for the IBS-D. All of these findings also provide the evidence concerning an inherent linkage between the axis of stress/NF-κB/inflammation and IBS-D.


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