TNF alpha inhibitors restrict T cell activation and cycling via Notch-1 signalling in inflammatory bowel disease

Background Tumour necrosis factor alpha (TNF alpha) inhibitors such as adalimumab and infliximab are frequently prescribed for inflammatory bowel disease (IBD). Despite the clinical success of TNF alpha inhibitors, their physiological mode of action is not fully understood. The aim of this study was to investigate the mode of action of anti-TNF alpha agents in IBD. Methods It was hypothesised that Notch mediates anti-TNF alpha action in T cells. A study was carried out to identify Notch-1 as a link by which anti-TNF alpha antibodies mediate their inhibitory functions. Results TNF alpha inhibitors induced T cell apoptosis, inhibited activation, reduced cytokine secretion and restricted cell cycling. TNF alpha blockade at several levels showed that TNF alpha is responsible for inducing apoptosis by anti-TNF alpha but not for cell cycle restriction. By linking Notch and TNF alpha it was shown that (1) Notch-1 mucosal expression differs in inflamed and non-inflamed mucosa and increases in response to anti-TNF alpha treatment; (2) Notch-1 function is regulated by TNF alpha inhibitors; (3) Notch-1 binds to TNF alpha; and (4) Notch-1 inhibition prevents anti-TNF alpha-induced T cell cycle arrest but not apoptosis. Conclusions TNF alpha 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.