title: TNFα inhibitors restrict T cell activation and cycling via Notch-1 signalling in inflammatory bowel disease.
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.
authors: Department of Medicine, Division of Gastroenterology and Hepatology, Charité Campus Virchow Clinic, Universitätsmedizin Berlin, Berlin, Germany.
authors: Lael
authors: L
authors: Werner
authors: Uta
authors: U
authors: Berndt
authors: Daniela
authors: D
authors: Paclik
authors: Silvio
authors: S
authors: Danese
authors: Anja
authors: A
authors: Schirbel
authors: Andreas
authors: A
authors: Sturm
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle; D059447:Cell Cycle Checkpoints; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D051881:Receptor, Notch1 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000893:Anti-Inflammatory Agents; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D014409:Tumor Necrosis Factor-alpha