In Esophageal Squamous Cells From Eosinophilic Esophagitis Patients, Th2 Cytokines Increase Eotaxin-3 Secretion Through Effects on Intracellular Calcium and a Non-Gastric Proton Pump.

摘要: Background & Aims In upper airway cells, T helper 2 cytokines that signal through interleukin-4 (IL-4) receptor-α have been shown to stimulate eotaxin-3 secretion via a nongastric proton pump (ngH+,K+ATPase). To seek novel targets for eosinophilic esophagitis (EoE) treatments, we evaluated ngH+,K+ATPase expression in EoE squamous and explored molecular pathways involved by IL-4 signaling. Methods cells was quantitative real-time polymerase chain reaction Western blotting. IL-4–stimulated measured enzyme-linked immunosorbent assay after treatment with omeprazole, SCH 28080 (potassium-competitive acid blocker), ethylene glycol-bis(β-aminoethyl)-N,N,N′,N′-tetraacetoxymethyl ester (calcium chelator), 2-aminoethoxydiphenyl borate (inhibitor of endoplasmic reticulum calcium release), verapamil, diltiazem (L-type channel inhibitors). Intracellular transients were Fluo-4 fluorescence. Key experiments confirmed primary RNA sequencing datasets from mucosal biopsies patients controls. Results expressed messenger protein. Omeprazole decreased secretion. increased intracellular transients, blocked ester, borate, diltiazem. The combination omeprazole verapamil suppressed more than either agent alone. higher exhibited signaling Conclusions express mediates cytokine–stimulated induces release the entry L-type channels, increasing contributes cells. inhibitors block secretion, suggesting potential role these agents treatment.