title: Blockade of Interplay between IL-17A and Endoplasmic Reticulum Stress Attenuates LPS-Induced Lung Injury.
abstract: IL-17 is a cytokine mainly from IL-17-producing T cells, which are one of subsets of CD4+ T cells and play a role in adaptive immune system. Recent studies have demonstrated that IL-17A can act rapidly as an innate immune responder during infection before the onset of its classic adaptive immune response. This role of IL-17A in innate immune response is implicated in lipopolysaccharide (LPS)-induced lung inflammation. Very recently, we have reported that endoplasmic reticulum (ER) stress is involved in LPS-induced lung inflammation in vivo and in vitro. This study aimed to elucidate the role of IL-17A in LPS-induced lung injury, focusing on the link with ER stress. We treated a murine model of LPS-induced lung injury with IL-17A neutralizing antibody and 4-phenylbutyrate (4-PBA), a representative ER stress inhibitor. In addition, we evaluated the effects of IL-17A on ER stress in LPS-stimulated bronchial epithelial cells. Our results showed that inhibition of IL-17A decreased LPS-induced pulmonary neutrophilia, vascular leakage, nuclear translocation of nuclear factor-κB (NF-κB), infiltration of dendritic cells, increased expression of Toll-like receptor 4 (TLR4), activation of NLRP3 inflammasome, and increased ER stress in the lung. 4-PBA or TAK-242, a TLR4 inhibitor attenuated expression of IL-17A thereby improving LPS-induced lung inflammation. Intriguingly, we observed that stimulation with LPS increased expression of IL-17A in airway epithelial cells and co-stimulation with IL-17A further increased ER stress and NF-κB activation. This study indicates that the interrelationship between IL-17A and ER stress plays an important role in LPS-induced injury showing a positive feedback in airway epithelial cells and suggests that targeting their interaction can be a potential therapeutic approach to overcome one of severe refractory pulmonary disorders.
authors.affiliation: 1. Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, San 2-20 Geumam-dong, Deokjin-gu, Jeonju, 561-180, South Korea;
authors.forename: So Ri
authors.initials: SR
authors.lastname: Kim
authors.affiliation: 1. Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, San 2-20 Geumam-dong, Deokjin-gu, Jeonju, 561-180, South Korea;
authors.forename: Hee Jung
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: 1. Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, San 2-20 Geumam-dong, Deokjin-gu, Jeonju, 561-180, South Korea;
authors.forename: Dong Im
authors.initials: DI
authors.lastname: Kim
authors.affiliation: 1. Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, San 2-20 Geumam-dong, Deokjin-gu, Jeonju, 561-180, South Korea;
authors.forename: Kyung Bae
authors.initials: KB
authors.lastname: Lee
authors.affiliation: 1. Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, San 2-20 Geumam-dong, Deokjin-gu, Jeonju, 561-180, South Korea;
authors.forename: Hae Jin
authors.initials: HJ
authors.lastname: Park
authors.affiliation: 1. Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, San 2-20 Geumam-dong, Deokjin-gu, Jeonju, 561-180, South Korea;
authors.forename: Jae Seok
authors.initials: JS
authors.lastname: Jeong
authors.affiliation: 2. Division of Allergy-Immunology, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
authors.forename: Seong Ho
authors.initials: SH
authors.lastname: Cho
authors.affiliation: 1. Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, San 2-20 Geumam-dong, Deokjin-gu, Jeonju, 561-180, South Korea;
authors.forename: Yong Chul
authors.initials: YC
authors.lastname: Lee
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D008168:Lung / Q000473:pathology; D055370:Lung Injury / Q000139:chemically induced*; D008810:Mice, Inbred C57BL; D010654:Phenylbutyrates / Q000008:administration & dosage
chemical_list: D020381:Interleukin-17; D008070:Lipopolysaccharides; D010654:Phenylbutyrates; C075773:4-phenylbutyric acid
keywords: ER stress; IL-17A; LPS; acute lung injury; epithelial cell; inflammation