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. Author manuscript; available in PMC: 2022 Apr 16.
Published in final edited form as: Gastroenterology. 2021 Feb 11;160(6):2072–2088.e6. doi: 10.1053/j.gastro.2021.02.016

Figure 7.

Figure 7.

Omeprazole (OME) in combination with verapamil (VER) has a significantly greater suppressive effect on IL-4–stimulated eotaxin-3 secretion than either agent alone in EoE2-T and primary EoE2-ALI cells. Representative eotaxin-3 enzyme-linked immunosorbent assays 24 hours after IL-4 treatment in (A) EoE-2T and (B) 48 hours after IL-4 treatment in primary EoE2-ALI cells with and without OME, VER, or the combination of both. Bar graphs depict the mean ± SEM from 3 separate samples for EoE2-T and from ALI cultures performed at least in triplicate from 1 male EoE patient. ***P ≤ .001 compared with control; +++P ≤ .001 compared with IL-4; ##P ≤ .01, ###P ≤ .001 compared with IL-4 + VER 50 μM; &&&P ≤ .001 compared with IL-4 + OME 50 μM; 1-way analysis of variance. (C) Representative H&E staining of primary EoE2-ALI cultures 48 hours after IL-4 treatment with and without OME, VER, or the combination of both. Scale bar: 75 μm. (D) Diagram demonstrating mechanisms whereby VER and diltiazem (L-type calcium channel blockers) in combination with PPIs and PCABs (inhibitors of the nongastric proton pump) block Th2 cytokine–stimulated eotaxin-3 secretion by esophageal squamous cells. IL-4 and IL-13 bind to the type II IL-4 receptor containing the IL4Rα subunit. This binding activates IL4Rα-mediated calcium signaling by causing IP3-mediated calcium release from the endoplasmic reticulum and by increasing entry of extracellular calcium through L-type calcium channels on the plasma membrane. The increase in intracellular calcium leads to an increase in eotaxin-3 production and secretion, at least in part via effects on activity of the nongastric proton pump. Verapamil and diltiazem block extracellular calcium entry through L-type calcium channels, thereby reducing intracellular calcium signaling, whereas the PPIs and the P-CABs inhibit nongastric proton pump activity, thus reducing Th2 cytokine–stimulated eotaxin-3 secretion. Agents that inhibit intracellular calcium signaling downstream of IL4Rα activation alone or in combination with inhibitors of the nongastric proton pump might have a therapeutic role in EoE (dashed arrow; potential mechanism based on literature review41).