INFLAMMATION AND INFLAMMATORY BOWEL DISEASE Tumour necrosis factor α potentiates ion secretion induced by histamine in a human intestinal epithelial cell line and in mouse colon: involvement of the phospholipase D pathway

Background and aims: Patients suffering from inflammatory bowel disease show increased levels of the mast cell products histamine and tumour necrosis factor α (TNF-α). Treating these patients with antibodies against TNF-α diminishes the symptoms of diarrhoea. In this study, the effect of TNF-α on ion secretion induced by the mast cell mediator histamine in HT29cl.19A cells and mouse distal colon was investigated and the possible second messengers involved were studied. Methods: Electrophysiology of filter grown HT29cl.19A cells and isolated mouse distal colon was used to monitor the secretory response to histamine with and without prior exposure to TNF-α for 3–24 hours. Phospholipase D (PLD) activity and phosphatidic acid levels were analysed by Pi labelling of HT29cl.19A cells. Results: In both experimental systems TNF-α was found to potentiate ion secretion induced by histamine. Phospholipid analysis of HT29cl.19A cells revealed that histamine activates the PLD pathway. Furthermore, TNF-α pretreated cells were found to have decreased phosphatidic acid levels, the intermediate product of the PLD pathway, which indicates upregulation of the enzyme phosphatidic acid phosphatase. Conclusions: The mast cell products TNF-α and histamine synergistically stimulate ion secretion in intestinal epithelium via upregulation of the PLD pathway.