Document Detail

TNFα inhibitors restrict T cell activation and cycling via Notch-1 signalling in inflammatory bowel disease.
MedLine Citation:
PMID:  22068169     Owner:  NLM     Status:  Publisher    
BackgroundTumour 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.MethodsIt 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.ResultsTNFα 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.ConclusionsTNFα 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.
Lael Werner; Uta Berndt; Daniela Paclik; Silvio Danese; Anja Schirbel; Andreas Sturm
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-11-7
Journal Detail:
Title:  Gut     Volume:  -     ISSN:  1468-3288     ISO Abbreviation:  -     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-11-9     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985108R     Medline TA:  Gut     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Division of Gastroenterology and Hepatology, Charité Campus Virchow Clinic, Universitätsmedizin Berlin, Berlin, Germany.
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