한빛사 논문
Abstract
Hyun-Woo Shin, MD, PhDa, b, *, Dong-Kyu Kim, MDc, *, Min-Hyun Park, MD, PhDd, Kyoung Mi Eun, BScd, Mingyu Lee, BSca, Daeho So, BSca, Il Gyu Kong, MD, PhDe, Ji-Hun Mo, MD, PhDf, Min-Suk Yang, MDg, Hong Ryul Jin, MD, PhDd, Jong-Wan Park, MD, PhDa, Dae Woo Kim, MD, PhDd
a Department of Pharmacology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea
b Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Korea
e Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Korea
c Department of Otorhinolaryngology, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon, Korea
d Department of Otorhinolaryngology-Head and Neck Surgery, Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
g Department of Internal Medicine, Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
f Department of Otorhinolaryngology, Dankook University College of Medicine, Chonan, Korea
*These authors contributed equally to this work.
Corresponding author: Dae Woo Kim, MD, PhD
Background
Chronic rhinosinusitis (CRS) with nasal polyps (NPs) in Western populations is associated with TH2 cytokine polarization. IL-25, an IL-17 family cytokine, was recently reported to induce TH2-type immune responses and to contribute to several allergic diseases, such as atopic dermatitis and asthma. However, the role of IL-25 in Asian patients with nasal polyposis remains unclear.
Objective
We sought to determine the role of IL-25 in Asian patients with nasal polyposis and CRS.
Methods
We investigated IL-25 expression and its cellular origins in NPs of human subjects using immunohistochemistry (IHC), quantitative RT-PCR, and ELISA of NP tissues. Correlations between IL-25 expression and expression of other inflammatory markers in NP tissues were also explored. Anti-IL-25 neutralizing antibody was administered in an ovalbumin- and staphylococcal enterotoxin B-induced murine NP model to confirm the function of IL-25 during nasal polypogenesis.
Results
IL-25 expression was upregulated in NP mucosa from patients with CRS with NPs compared with uncinate process tissue from control subjects and those with CRS without NPs. Overexpression of epithelial IL-25 was confirmed by using IHC, and double IHC staining showed that tryptase-positive cells were one of the main sources of IL-25 among immune cells. Furthermore, IL-17 receptor B levels were also increased in immune cells of patients with NPs compared with those in control subjects. In NPs IL-25 mRNA expression positively correlated with the expression of several inflammatory markers, including T-box transcription factor, RAR-related orphan receptor C, GATA3, eosinophil cationic protein, TGF-β1, and TGF-β2. IL-25 was more abundant in the murine NP model compared with control mice, and similar correlations between IL-25 and inflammatory markers were observed in murine models. Anti-IL-25 treatment reduced the number of polyps, mucosal edema thickness, collagen deposition, and infiltration of inflammatory cells, such as eosinophils and neutrophils. This treatment also inhibited expression of local inflammatory cytokines, such as IL-4 and IFN-γ. Furthermore, expression of CCL11, CXCL2, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 in the nasal mucosa was suppressed in the anti-IL-25-treated group.
Conclusion
Our results suggest that IL-25 secreted from the sinonasal epithelia and infiltrating mast cells plays a crucial role in the pathogenesis of CRS with NPs in Asian patients. In addition, our results suggest the novel possibility of treating nasal polyposis with anti-IL-25 therapy.
Key words : Nasal polyp; IL-25; sinusitis; allergy; animal models
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