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Int Immunopharmacol. 2019 May;70:88-100. doi: 10.1016/j.intimp.2019.02.022. Epub 2019 Feb 20.

Beneficial effects of dual TORC1/2 inhibition on chronic experimental colitis.

Author information

1
Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 200025 Shanghai, PR China; Translational Gastroenterology Research Unit, GIGA-R, University of Liège, Belgium.
2
Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 200025 Shanghai, PR China; Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and technology, Wuhan, Hubei, PR China.
3
Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 200025 Shanghai, PR China.
4
Translational Gastroenterology Research Unit, GIGA-R, University of Liège, Belgium; Hepato-Gastroenterology and Digestive Oncology Unit, University Hospital, CHU Liege, Domaine du Sart Tilman, 4000 Liege, Belgium. Electronic address: Edouard.louis@ulg.ac.be.
5
Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 200025 Shanghai, PR China. Electronic address: jimmyzj64@hotmail.com.

Abstract

BACKGROUND AND AIM:

AZD8055, a new immunosuppressive reagent, a dual TORC1/2 inhibitor, had been used successfully in animal models for heart transplantation. The aim of this study was to evaluate the effects and mechanisms of AZD8055 on chronic intestinal inflammation.

METHODS:

Dextran sulfate sodium (DSS) - induced chronic colitis was used to investigate the effects of AZD8055 on the development of colitis. Colitis activity was monitored by body weight assessment, colon length, histology and cytokine profile analysis.

RESULTS:

AZD8055 treatment significantly alleviated the severity of colitis, as assessed by colonic length and colonic damage. In addition, AZD8055 treatment decreased the colonic CD4+ T cell numbers and reduced both Th1 and Th17 cell activation and cytokine production. The percentages of Treg cells in the colon were also expanded by AZD8055 treatment. Furthermore, AZD8055 effectively inhibited mTOR downstream proteins and signal transducer and activator of transcription related proteins in CD4+ T cells of intestinal lamina propria.

CONCLUSIONS:

These findings increased our understanding of DSS-induced colitis and shed new lights on mechanisms of digestive tract chronic inflammation. Dual TORC1/2 inhibition showed potent anti-inflammatory and immune regulation effects by targeting critical signaling pathways. The results supported the strategy of using dual mTOR inhibitor to treat inflammatory bowel disease.

KEYWORDS:

AZD8055; Chronic colitis; Inflammatory bowel disease; JAK/STAT; mTOR

PMID:
30797172
DOI:
10.1016/j.intimp.2019.02.022
[Indexed for MEDLINE]

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