Abstract
The P-STS human ileal neuroendocrine tumor cells, as a model for gut enterochromaffin cells, are strongly and synergistically activated by histamine plus acetylcholine (ACh), presumably via histamine 4 receptors, and weakly activated by histamine alone. Sensing these signals, enterochromaffin cells could participate in intestinal intolerance or allergic reactions to food constituents associated with elevated histamine levels. In this study we aimed to analyze the underlying molecular mechanisms. Inhibition by mepyramine and mibefradil indicated that histamine alone caused a rise in intracellular calcium concentration ([Ca2+]i) via histamine 1 receptors involving T-type voltage-gated calcium channels (VGCCs). Sensitivity to histamine was enhanced by pretreatment with the inflammatory cytokine tumor necrosis factor-α (TNF-α). In accordance with the relief it offers some inflammatory bowel disease patients, otilonium bromide, a gut-impermeable inhibitor of T-type (and L-type) VGCCs and muscarinic ACh receptors, efficiently inhibited the [Ca2+]i responses induced by histamine plus ACh or by histamine alone in P-STS cells. It will take clinical studies to show whether otilonium bromide has promise for the treatment of adverse food reactions. The cells did not react to the nutrient constituents glutamate, capsaicin, cinnamaldehyde, or amylase-trypsin inhibitors and the transient receptor potential channel vanilloid 4 agonist GSK-1016790A. The bacterial product butyrate evoked a rise in [Ca2+]i only when added together with ACh. Lipopolysaccharide had no effect on [Ca2+]i despite the presence of Toll-like receptor 4 protein. Our results indicate that inflammatory conditions with elevated levels of TNF-α might enhance histamine-induced serotonin release from intestinal neuroendocrine cells. NEW & NOTEWORTHY We show that histamine synergistically enhances the intracellular calcium response to the physiological agonist acetylcholine in human ileal enterochromaffin tumor cells. This synergistic activation and cell activation by histamine alone largely depend on T-type voltage-gated calcium channels and are inhibited by the antispasmodic otilonium bromide. The cells showed no response to wheat amylase-trypsin inhibitors, suggesting that enterochromaffin cells are not directly involved in nongluten wheat sensitivity.
Highlights
At present, the triggers of adverse food reactions in individual patients are not entirely predictable
In our previous work [44] we showed that histamine 3 receptor (H3R) activation had an inhibitory effect on the [Ca2ϩ]i response of
This suggests that pulses of ACh secreted by nerve endings and reaching EC cells located in intestinal crypts could evoke a similar response when histamine concentrations are elevated following mast cell activation
Summary
The triggers of adverse food reactions in individual patients are not entirely predictable. Innate mechanisms and neuronal factors may amplify the reactions, especially with preexisting inflammatory conditions. EC cells are dispersed throughout the intestinal mucosa and release serotonin (5-hydroxytryptamine) to the serosal side upon stimulation by nutrients or other chemical mediators, acidic pH, or mechanical distortion [6, 25]. Their apical microvilli project in the gut lumen. They are found in close contact to nerve endings of submucosal neurons of the enteric reflex pathways, which are largely cholinergic [26, 36]. A role of serotonin in the pathology of inflammatory bowel disease, diarrhea-predominant irritable bowel syndrome (IBS), and celiac disease is discussed [19, 20, 30]
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