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

Shurong Hu1, Mengmeng Cheng2, Rong Fan3

  • 1Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 200025 Shanghai, PR China; Translational Gastroenterology Research Unit, GIGA-R, University of Liège, Belgium.

International Immunopharmacology
|February 24, 2019
PubMed
Abstract

Insights

AZD8055, a dual TORC1/2 inhibitor, effectively reduced chronic intestinal inflammation in a dextran sulfate sodium (DSS)-induced colitis model. This immunosuppressive reagent modulated T cell populations and signaling pathways, supporting its potential for treating inflammatory bowel disease.

Area of Science:

  • Immunology
  • Gastroenterology
  • Pharmacology

Background:

  • AZD8055 is a dual inhibitor of mammalian target of rapamycin (mTOR) complex 1/2 (TORC1/2).
  • Previous studies demonstrated its efficacy in animal models of heart transplantation.
  • Chronic intestinal inflammation, such as inflammatory bowel disease (IBD), remains a significant clinical challenge.

Purpose of the Study:

  • To investigate the therapeutic effects of AZD8055 on dextran sulfate sodium (DSS)-induced chronic colitis.
  • To elucidate the underlying immune regulatory mechanisms of AZD8055 in the intestinal tract.

Main Methods:

  • A mouse model of DSS-induced chronic colitis was employed.
  • AZD8055 treatment effects were evaluated through body weight, colon length, histology, and cytokine analysis.
  • Immune cell populations (CD4+ T cells, Treg cells) and signaling pathways (mTOR, STAT) in the intestinal lamina propria were assessed.

Main Results:

  • AZD8055 significantly ameliorated colitis severity, reducing colonic damage and shortening.
  • Treatment decreased CD4+ T cell numbers and suppressed Th1/Th17 cell activation and cytokine production.
  • AZD8055 expanded regulatory T cell (Treg) populations and inhibited key downstream signaling proteins in intestinal CD4+ T cells.

Conclusions:

  • Dual TORC1/2 inhibition with AZD8055 demonstrates potent anti-inflammatory and immune-regulatory effects in chronic intestinal inflammation.
  • The drug targets critical signaling pathways, offering a promising strategy for IBD treatment.
  • These findings enhance understanding of DSS-induced colitis and chronic digestive tract inflammation mechanisms.
Keywords:
AZD8055Chronic colitisInflammatory bowel diseaseJAK/STATmTOR

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