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mTOR Inhibition Attenuates Dextran Sulfate Sodium-Induced Colitis by Suppressing T Cell Proliferation and Balancing

Shurong Hu1, Mengmeng Chen1, Yilin Wang2

  • 1Department of Gastroenterology, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.

Plos One
|April 30, 2016
PubMed

Insights

AZD8055, an mTOR inhibitor, reduces inflammation in experimental colitis by regulating T cell responses. This drug decreases pro-inflammatory T cells and increases regulatory T cells, offering a potential therapeutic strategy for inflammatory bowel diseases.

Area of Science:

  • Immunology
  • Gastroenterology
  • Pharmacology

Background:

  • Mammalian target of Rapamycin (mTOR) inhibitors show anti-inflammatory effects in experimental colitis models.
  • The precise mechanisms underlying these effects, particularly concerning T cell responses, remain largely unelucidated.
  • Inflammatory bowel diseases (IBD) are chronic inflammatory conditions of the gastrointestinal tract.

Purpose of the Study:

  • To investigate the anti-inflammatory effects of AZD8055, a potent mTOR inhibitor, on T cell responses in a dextran sulfate sodium (DSS)-induced mouse model of colitis.
  • To elucidate the mechanisms by which AZD8055 modulates T cell polarization, proliferation, and regulatory function in the context of experimental colitis.

Main Methods:

  • Induction of experimental colitis in mice using DSS.
  • Administration of AZD8055 and evaluation of colitis severity via body weight, stool consistency, and colon histology.
  • Analysis of cytokine expression in colonic tissue.
  • Flow cytometry analysis of T cell populations (CD4+, CD8+, TH1, TH17, Treg) in spleen, lymph nodes, peripheral blood, and colonic lamina propria.
  • In vitro assessment of AZD8055's effects on T cell proliferation and differentiation.

Main Results:

  • AZD8055 treatment significantly attenuated DSS-induced colitis severity, including weight loss, colon shortening, and pathological damage.
  • AZD8055 decreased colonic expression of pro-inflammatory cytokines (IFN-γ, IL-17A, IL-1β, IL-6, TNF-α) and increased anti-inflammatory IL-10.
  • AZD8055 reduced percentages of CD4+ and CD8+ T cells, decreased TH1 and TH17 cells, and increased regulatory T (Treg) cells in various tissues.
  • In vitro studies confirmed that AZD8055 suppresses T cell proliferation and TH1/TH17 differentiation while promoting Treg expansion.

Conclusions:

  • AZD8055 demonstrates significant anti-inflammatory effects in experimental colitis.
  • The therapeutic action of AZD8055 is mediated through the regulation of T helper cell polarization and proliferation.
  • These findings suggest AZD8055 as a potential therapeutic agent for inflammatory bowel diseases by modulating adaptive immune responses.

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