TGF-β1–induced phospholamban expression alters esophageal smooth muscle cell contraction in patients with eosinophilic esophagitis Lisa Y. Beppu, BS,

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TGF-β1–induced phospholamban expression alters esophageal smooth muscle cell contraction in patients with eosinophilic esophagitis Lisa Y. Beppu, BS, Arjun A. Anilkumar, BS, Robert O. Newbury, MD, Ranjan Dohil, MD, David H. Broide, MBChB, Seema S. Aceves, MD, PhD Journal of Allergy and Clinical Immunology Volume 134, Issue 5, Pages 1100-1107.e4 (November 2014) DOI: 10.1016/j.jaci.2014.04.004 Copyright © 2014 Terms and Conditions

Fig 1 TGF-β1 induces PLN in ESM cells and EMFs from patients with EoE. A and B, PLN mRNA (Fig 1, A) and protein (Fig 1, B) are detected in primary ESM cells after TGF-β1 treatment. H, Cardiac extract positive control. C and D, Primary fibroblasts from patients with EoE express αSMA (green; blue, nuclear 4′-6-diamidino-2-phenylindol dihydrochloride; Fig 1, C) and PLN (green), which colocalizes (yellow) with αSMA (red) on TGF-β1 treatment (Fig 1, D). Protein molecular weight ladder shows PLN monomer of less than the 5-kDa marker. Isotype control (insets) shows no staining. Gapdh, Glyceraldehyde-3-phosphate dehydrogenase. Journal of Allergy and Clinical Immunology 2014 134, 1100-1107.e4DOI: (10.1016/j.jaci.2014.04.004) Copyright © 2014 Terms and Conditions

Fig 2 PLN is expressed in smooth muscle from patients with EoE and localizes with Serca2a. A and B, Representative image (Fig 2, A) and quantification (Fig 2, B) of smooth muscle PLN in control biopsy specimens and esophageal biopsy specimens from patients with EoE. C, PLN (green) colocalizes (yellow) with αSMA (red). D, PLN (green) colocalizes (yellow) with Serca2a (red) in pediatric patients with EoE. Inset shows nuclear 4′-6-diamidino-2-phenylindol dihydrochloride staining. EPI, Epithelium; LP, lamina propria; SM, smooth muscle. Journal of Allergy and Clinical Immunology 2014 134, 1100-1107.e4DOI: (10.1016/j.jaci.2014.04.004) Copyright © 2014 Terms and Conditions

Fig 3 PLN downregulation significantly decreases esophageal EMF cell contraction in patients with EoE. A, PLN siRNA inhibits TGF-β1–induced PLN expression (representative Western blot). GAPDH, Glyceraldehyde-3-phosphate dehydrogenase. B and C, TGF-β1–induced contraction of EMFs from patients with EoE (representative contraction gel; Fig 3, B) is significantly decreased by PLN siRNA but not by control siRNA (Fig 3, C). Graphs represent means and SEs. Journal of Allergy and Clinical Immunology 2014 134, 1100-1107.e4DOI: (10.1016/j.jaci.2014.04.004) Copyright © 2014 Terms and Conditions

Fig 4 TGF-βRI and TGF-βRII are expressed on ESM cells and required for TGF-β1–mediated contraction, as well as PLN phosphorylation. A, FACS analysis (black plot, isotype control; gray plot, specific antibody) demonstrates that ESM cells and fibroblasts from patients with EoE express TGF-βRI and TGF-βRII. B, TGF-βRI (red) and TGF-βRII (green) are coexpressed (yellow) on fibroblasts from patients with EoE. C, Representative image of EoE biopsy specimen shows colocalization (yellow) of TGF-βRI (red) and TGF-βRII (green) receptors in ESM cells (insets show isotype control). D and E, TGF-βRI inhibitor, but not TAK1 inhibitor, abolishes PLN expression induced by TGF-β1 (Fig 4, D), but TAK1 inhibitor does block c-Jun N-terminal kinase phosphorylation by IL-1β (Fig 4, E). GAPDH, Glyceraldehyde-3-phosphate dehydrogenase. F, TGF-βRI inhibitors block ESM contraction, but TAK1 inhibitor does not. Journal of Allergy and Clinical Immunology 2014 134, 1100-1107.e4DOI: (10.1016/j.jaci.2014.04.004) Copyright © 2014 Terms and Conditions

Fig 5 TGF-β1 causes PLN phosphorylation. A and B, Phospho-serine-16 is detectable after TGF-β1 treatment (Fig 5, A), but phospho-threonine-17 is not (Fig 5, B). The heart (H) was used a positive control to detect phospho-threonine-17-PLN. GAPDH, Glyceraldehyde-3-phosphate dehydrogenase. C, A representative image demonstrates that phospho-serine-16 is expressed in ESM from patients with EoE but not in control ESM. Journal of Allergy and Clinical Immunology 2014 134, 1100-1107.e4DOI: (10.1016/j.jaci.2014.04.004) Copyright © 2014 Terms and Conditions

Fig 6 Model of the pathway by which TGF-β1 could regulate or alter ESM and myofibroblast function. TGF-β1 produced by mast cells and eosinophils binds to its receptor (TGF-βRI), causing PLN transcription through the phosphorylated Smad pathway and colocalization of PLN with the calcium channel Serca2a. PLN phosphorylation (P-PLN) and dephosphorylation change calcium flux into the sarcoplasmic reticulum through Serca2a. Intracellular calcium changes could cause ESM cell and myofibroblast contraction to cause esophageal dysmotility and tissue contraction. MC, Mast cell. Journal of Allergy and Clinical Immunology 2014 134, 1100-1107.e4DOI: (10.1016/j.jaci.2014.04.004) Copyright © 2014 Terms and Conditions

Fig E1 TGF-β1 induces PLN in EMFs from patients with EoE. Representative time course of PLN mRNA (A) and protein (B) after treatment of EMFs from patients with EoE is shown. Gapdh, Glyceraldehyde-3-phosphate dehydrogenase Journal of Allergy and Clinical Immunology 2014 134, 1100-1107.e4DOI: (10.1016/j.jaci.2014.04.004) Copyright © 2014 Terms and Conditions

Fig E2 TGF-βRI but not TAK1 inhibition abolishes EMF cell contraction in patients with EoE. EMF cells from patients with EoE treated with TGF-β1 have EMF-impregnated gel contraction that is inhibited by pharmacologic inhibition of TGF-βRI but not TAK1. NS, Not significant. Journal of Allergy and Clinical Immunology 2014 134, 1100-1107.e4DOI: (10.1016/j.jaci.2014.04.004) Copyright © 2014 Terms and Conditions