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TNFα inhibitors restrict T cell activation and cycling via Notch-1 signalling in inflammatory bowel disease
  1. Lael Werner1,
  2. Uta Berndt1,
  3. Daniela Paclik1,
  4. Silvio Danese2,
  5. Anja Schirbel1,
  6. Andreas Sturm1
  1. 1Department of Medicine, Division of Gastroenterology and Hepatology, Charité Campus Virchow Clinic, Universitätsmedizin Berlin, Berlin, Germany
  2. 2Division of Gastroenterology, IRCCS Istituto Clinico Humanitas, Rozzano, Milan, Italy
  1. Correspondence to Professor Dr med Andreas Sturm, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; andreas.sturm{at}charite.de

Abstract

Background Tumour necrosis factor α (TNFα) inhibitors such as adalimumab and infliximab are frequently prescribed for inflammatory bowel disease (IBD). Despite the clinical success of TNFα inhibitors, their physiological mode of action is not fully understood. The aim of this study was to investigate the mode of action of anti-TNFα agents in IBD.

Methods It was hypothesised that Notch mediates anti-TNFα action in T cells. A study was carried out to identify Notch-1 as a link by which anti-TNFα antibodies mediate their inhibitory functions.

Results TNFα inhibitors induced T cell apoptosis, inhibited activation, reduced cytokine secretion and restricted cell cycling. TNFα blockade at several levels showed that TNFα is responsible for inducing apoptosis by anti-TNFα but not for cell cycle restriction. By linking Notch and TNFα it was shown that (1) Notch-1 mucosal expression differs in inflamed and non-inflamed mucosa and increases in response to anti-TNFα treatment; (2) Notch-1 function is regulated by TNFα inhibitors; (3) Notch-1 binds to TNFα; and (4) Notch-1 inhibition prevents anti-TNFα-induced T cell cycle arrest but not apoptosis.

Conclusions TNFα inhibitors potently inhibit T cell function. By demonstrating for the first time that Notch-1 mediates the inhibitory effects of adalimumab and infliximab on T cell cycling, this study reveals a new mode of action and also an underlying signalling pathway by which biological agents act in IBD.

  • Inflammatory bowel disease
  • TNFα inhibitors
  • adalimumab
  • infliximab
  • notch
  • T cells
  • cell cycle

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Footnotes

  • Funding This work was partially sponsored by a fellowship (LW) of the European Crohn's and Colitis Organization (ECCO) and an unrestricted scientific grant of Abbott. The funding source had no influence on the study.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics committee of the Charité Hospital.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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