Tags

Type your tag names separated by a space and hit enter

The IFN-γ-p38, ERK kinase axis exacerbates neutrophilic chronic rhinosinusitis by inducing the epithelial-to-mesenchymal transition.
Mucosal Immunol 2019; 12(3):601-611MI

Abstract

Chronic rhinosinusitis (CRS) is a heterogeneous and multifactorial inflammatory disease characterized by involvement of diverse types of inflammatory cells. Asian CRS patients frequently show infiltration of neutrophils and an elevated level of interferon (IFN)-γ; by contrast, western patients exhibit eosinophil infiltration and enhanced levels of Th2-related cytokines. Neutrophilia in tissues decreases sensitivity to corticosteroids, but the mechanisms underlying the progression of neutrophilic CRS are unclear. In this study, we investigated the role of IFN-γ in CRS patients with marked neutrophil infiltration. We report that the IFN-γ level is upregulated in the tissues of these patients, particularly those with non-eosinophilic nasal polyps. The level of IFN-γ was significantly correlated with markers of the epithelial-to-mesenchymal transition (EMT). We further demonstrated that IFN-γ induced the EMT via the p38 and extracellular signal-regulated kinase (ERK) pathways in a manner distinct from the hypoxia-inducible factor (HIF)-1α, SMAD, and NF-κB signaling pathways. In a murine nasal polyp (NP) model, blocking the p38 and ERK signaling pathways prevented NP formation and chemotactic cytokine secretion by neutrophils but not eosinophils. Taken together, our results suggest that IFN-γ can induce the EMT in nasal epithelial cells, and thus blocking the p38 and ERK pathways could be an effective therapeutic strategy against neutrophil-dominant CRS.

Authors+Show Affiliations

Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea. Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.Department of Otorhinolaryngology-Head and Neck Surgery, Boramae Medical Center, Seoul, Korea.Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.Department of Otorhinolaryngology-Head and Neck Surgery, Chungnam National University Hospital, Daejun, Korea.Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Korea.Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Korea.Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Korea.Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Bundang Hospital, Seongnam, Korea.Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea. Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea.Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea. charlie@snu.ac.kr. Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea. charlie@snu.ac.kr. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. charlie@snu.ac.kr. Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Korea. charlie@snu.ac.kr. Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea. charlie@snu.ac.kr.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30804419

Citation

Lee, Mingyu, et al. "The IFN-γ-p38, ERK Kinase Axis Exacerbates Neutrophilic Chronic Rhinosinusitis By Inducing the Epithelial-to-mesenchymal Transition." Mucosal Immunology, vol. 12, no. 3, 2019, pp. 601-611.
Lee M, Kim DW, Khalmuratova R, et al. The IFN-γ-p38, ERK kinase axis exacerbates neutrophilic chronic rhinosinusitis by inducing the epithelial-to-mesenchymal transition. Mucosal Immunol. 2019;12(3):601-611.
Lee, M., Kim, D. W., Khalmuratova, R., Shin, S. H., Kim, Y. M., Han, D. H., ... Shin, H. W. (2019). The IFN-γ-p38, ERK kinase axis exacerbates neutrophilic chronic rhinosinusitis by inducing the epithelial-to-mesenchymal transition. Mucosal Immunology, 12(3), pp. 601-611. doi:10.1038/s41385-019-0149-1.
Lee M, et al. The IFN-γ-p38, ERK Kinase Axis Exacerbates Neutrophilic Chronic Rhinosinusitis By Inducing the Epithelial-to-mesenchymal Transition. Mucosal Immunol. 2019;12(3):601-611. PubMed PMID: 30804419.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The IFN-γ-p38, ERK kinase axis exacerbates neutrophilic chronic rhinosinusitis by inducing the epithelial-to-mesenchymal transition. AU - Lee,Mingyu, AU - Kim,Dae Woo, AU - Khalmuratova,Roza, AU - Shin,Seung-Hyun, AU - Kim,Yong-Min, AU - Han,Doo Hee, AU - Kim,Hyun-Jik, AU - Kim,Dong-Young, AU - Rhee,Chae-Seo, AU - Park,Jong-Wan, AU - Shin,Hyun-Woo, Y1 - 2019/02/25/ PY - 2018/01/30/received PY - 2019/02/04/accepted PY - 2019/01/25/revised PY - 2019/2/26/pubmed PY - 2019/8/28/medline PY - 2019/2/27/entrez SP - 601 EP - 611 JF - Mucosal immunology JO - Mucosal Immunol VL - 12 IS - 3 N2 - Chronic rhinosinusitis (CRS) is a heterogeneous and multifactorial inflammatory disease characterized by involvement of diverse types of inflammatory cells. Asian CRS patients frequently show infiltration of neutrophils and an elevated level of interferon (IFN)-γ; by contrast, western patients exhibit eosinophil infiltration and enhanced levels of Th2-related cytokines. Neutrophilia in tissues decreases sensitivity to corticosteroids, but the mechanisms underlying the progression of neutrophilic CRS are unclear. In this study, we investigated the role of IFN-γ in CRS patients with marked neutrophil infiltration. We report that the IFN-γ level is upregulated in the tissues of these patients, particularly those with non-eosinophilic nasal polyps. The level of IFN-γ was significantly correlated with markers of the epithelial-to-mesenchymal transition (EMT). We further demonstrated that IFN-γ induced the EMT via the p38 and extracellular signal-regulated kinase (ERK) pathways in a manner distinct from the hypoxia-inducible factor (HIF)-1α, SMAD, and NF-κB signaling pathways. In a murine nasal polyp (NP) model, blocking the p38 and ERK signaling pathways prevented NP formation and chemotactic cytokine secretion by neutrophils but not eosinophils. Taken together, our results suggest that IFN-γ can induce the EMT in nasal epithelial cells, and thus blocking the p38 and ERK pathways could be an effective therapeutic strategy against neutrophil-dominant CRS. SN - 1935-3456 UR - https://www.unboundmedicine.com/medline/citation/30804419/The_IFN-γ-p38,_ERK_kinase_axis_exacerbates_neutrophilic_chronic_rhinosinusitis_by_inducing_the_epithelial-to-mesenchymal_transition L2 - http://dx.doi.org/10.1038/s41385-019-0149-1 DB - PRIME DP - Unbound Medicine ER -