2033 IFN-gamma contributes to nasal polypogenesis by inducing epithelial-to-mesenchymal transition via non-smad pathway

Thursday, 15 October 2015
Hall D1 Foyer (Floor 3) (Coex Convention Center)

Mingyu Lee, BS , Department of Pharmacology, Seoul National Universtiy College of Medicine, Seoul, South Korea

Roza Khalmuratova, MD, PhD , Department of Pharmacology, Seoul National University, Seoul, South Korea

Dae Woo Kim, MD, PhD , Otorhinolaryngology-Head and Neck Surgery, Boramae Medical Center, Seoul, South Korea

Hyun-Woo Shin, MD, PhD , Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, South Korea

Purpose: Nasal polyps (NP) imply a refractory clinical course in a case of chronic rhinosinusitis (CRS). Although, numerous etiologic factors including allergy, infection and hypoxia associate with nasal polyps (NP), the mechanism underlying NP is not fully understood. Previously, we reported that hypoxia-induced epithelial-to-mesenchymal transition (EMT) is frequently observed in Asian NPs, and HIF-1α could be a therapeutic target for nasal polyposis (Ref 1). However, the nasal epithelial cells in NP patients are not only exposed to hypoxia but also to diverse types or combinations of inflammatory milieu. So we hypothesized that specific immunologic endotypes could induce or accelerate EMT in nasal epithelial cells, and lead to nasal polyp formation.

Methods: Human nasal epithelial cells (hNEC), RPMI2650 and A549 cell lines were used. Immunoblotting, immunofluorescence and immunohistochemistry were done to evaluate EMT markers and signaling molecules in vitro and in sinonasal tissues from CRS patients with or without NP. Boyden transwell system was utilized to measure the capacity of migration.

Results: Four different cytokines, IL-5, IL-17, TNF-α and IFN-γ, were treated to both hNEC and RPMI2650 cells respectively, and EMT markers were traced. Among them, IFN-γ could most induce EMT, which was confirmed by the spindle-shape of cell morphology, modest cytoskeleton rearrangement, increased migration potential and EMT marker changes. Mechanistically, IFN-γ-induced EMT via ERK and p38 pathway, which were known as non-smad pathway of EMT. Next, we investigated whether p38 and ERK inhibitors could prevent EMT phenomenon. Actually, both p38 inhibitor (SB203580) and ERK inhibitor (PD98059) suppressed IFN-γ-driven EMT. Finally, we checked IFN-γ and EMT marker levels in human nasal mucosa tissues. IFN-γ expression was upregulated in NP mucosa compared with tissues of control and CRS only patients. In addition, this IFN-γ expression was found to correlate with E-cadherin (an epithelial marker) loss and α-smooth muscle actin (a mesenchymal marker) expression.

Conclusion: IFN-γ induce EMT in hNEC and this process is critically mediated by ERK and p38 pathway. This study shows that IFN-γ-induced EMT is likely to contribute to nasal polyposis in CRS, and suggests that p38 and ERK inhibitors be viewed as a therapeutic target for nasal polyposis.

Ref. 1. Shin HW et al., Hypoxia-inducible Factor 1 Mediates Nasal Polypogenesis by Inducing epithelial-to-Mesenchymal Transition. Amer J Resp Crit Care Med, 2012, p944-954.