title: Allergen-induced resistin-like molecule-α promotes esophageal epithelial cell hyperplasia in eosinophilic esophagitis.
abstract: Resistin-like molecule (Relm)-α is a secreted, cysteine-rich protein belonging to a newly defined family of proteins, including resistin, Relm-β, and Relm-γ. Although resistin was initially defined based on its insulin-resistance activity, the family members are highly induced in various inflammatory states. Earlier studies implicated Relm-α in insulin resistance, asthmatic responses, and intestinal inflammation; however, its function still remains an enigma. We now report that Relm-α is strongly induced in the esophagus in an allergen-challenged murine model of eosinophilic esophagitis (EoE). Furthermore, to understand the in vivo role of Relm-α, we generated Relm-α gene-inducible bitransgenic mice by using lung-specific CC-10 promoter (CC10-rtTA-Relm-α). We found Relm-α protein is significantly induced in the esophagus of CC10-rtTA-Relm-α bitransgenic mice exposed to doxycycline food. The most prominent effect observed by the induction of Relm-α is epithelial cell hyperplasia, basal layer thickness, accumulation of activated CD4(+) and CD4(-) T cell subsets, and eosinophilic inflammation in the esophagus. The in vitro experiments further confirm that Relm-α promotes primary epithelial cell proliferation but has no chemotactic activity for eosinophils. Taken together, our studies report for the first time that Relm-α induction in the esophagus has a major role in promoting epithelial cell hyperplasia and basal layer thickness, and the accumulation of activated CD4(+) and CD4(-) T cell subsets may be responsible for partial esophageal eosinophilia in the mouse models of EoE. Notably, the epithelial cell hyperplasia and basal layer thickness are the characteristic features commonly observed in human EoE.
authors.affiliation: University of Cincinnati College of Medicine, Cincinnati, Ohio;
authors.forename: Parm
authors.initials: P
authors.lastname: Mavi
authors.affiliation: Allergy and Immunology, Cincinnati Children's Medical Center, Cincinnati, Ohio; and.
authors.forename: Rituraj
authors.initials: R
authors.lastname: Niranjan
authors.affiliation: Section of Pulmonary Diseases, Department of Medicine, Tulane Eosinohilic Disorder Center, Tulane University School of Medicine, New Orleans, Louisiana;
authors.forename: Parmesh
authors.initials: P
authors.lastname: Dutt
authors.affiliation: Section of Pulmonary Diseases, Department of Medicine, Tulane Eosinohilic Disorder Center, Tulane University School of Medicine, New Orleans, Louisiana;
authors.forename: Asifa
authors.initials: A
authors.lastname: Zaidi
authors.affiliation: Section of Pulmonary Diseases, Department of Medicine, Tulane Eosinohilic Disorder Center, Tulane University School of Medicine, New Orleans, Louisiana;
authors.forename: Jai Shankar
authors.initials: JS
authors.lastname: Shukla
authors.affiliation: Perinatal Institute, Cincinnati Children's Medical Center, Cincinnati, Ohio.
authors.forename: Thomas
authors.initials: T
authors.lastname: Korfhagen
authors.affiliation: Section of Pulmonary Diseases, Department of Medicine, Tulane Eosinohilic Disorder Center, Tulane University School of Medicine, New Orleans, Louisiana; Anil.Mishra@tulane.edu.
authors.forename: Anil
authors.initials: A
authors.lastname: Mishra
mesh_terms: D000485:Allergens / Q000633:toxicity*; D000818:Animals; D018791:CD4 Lymphocyte Count; D049109:Cell Proliferation; D002478:Cells, Cultured; D002633:Chemotaxis; D004318:Doxycycline / Q000633:toxicity*; D057765:Eosinophilic Esophagitis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004804:Eosinophils / Q000502:physiology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004947:Esophagus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006965:Hyperplasia / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D000485:Allergens; D036341:Intercellular Signaling Peptides and Proteins; C413576:Retnla protein, mouse; D004318:Doxycycline
keywords: eosinophils; epithelial cells; esophagus