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Theranostics 2015; 5(12):1343-1362. doi:10.7150/thno.11685 This issue Cite

Research Paper

Blockade of Interplay between IL-17A and Endoplasmic Reticulum Stress Attenuates LPS-Induced Lung Injury

So Ri Kim^1*✉, Hee Jung Kim^1*, Dong Im Kim¹, Kyung Bae Lee¹, Hae Jin Park¹, Jae Seok Jeong¹, Seong Ho Cho², Yong Chul Lee^1✉

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;
2. Division of Allergy-Immunology, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
^* These authors contributed equally to this work.

✉ Corresponding authors: Yong Chul Lee, MD, PhD. Department of Internal Medicine, Chonbuk National University Medical School, san 2-20, Geumam-dong, Deokjin-gu, Jeonju, 561-180, South Korea. Phone: 82-63-250-1664; Fax: 82-63-259-3212; E-mail: leeycac.kr. So Ri Kim, MD, PhD. Department of Internal Medicine, Chonbuk National University Medical School, san 2-20, Geumam-dong, Deokjin-gu, Jeonju, 561-180, South Korea. Phone: 82-63-250-2475; Fax: 82-63-259-3212; E-mail: soriac.kr. More

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.

Keywords: IL-17A, ER stress, LPS, inflammation, epithelial cell, acute lung injury

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