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Original article
The role of interleukin-33 in chronic rhinosinusitis
  1. Dong-Kyu Kim1,2,
  2. Hong Ryul Jin3,
  3. Kyoung Mi Eun3,
  4. Ji-Hun Mo2,4,5,
  5. Seong H Cho6,
  6. Sohee Oh7,
  7. David Cho3,
  8. Dae Woo Kim2,3
  1. 1Department of Otorhinolaryngology-Head and Neck Surgery, Chuncheon Sacred Heart Hospital and Nano-Bio Regenerative Medical Institute, Hallym University College of Medicine, Chuncheon, Republic of Korea
  2. 2Clinical Mucosal Immunology Study Group, Seoul, Republic of Korea
  3. 3Department of Otorhinolaryngology-Head and Neck Surgery, Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
  4. 4Department of Otorhinolaryngology, Dankook University College of Medicine, Chonan, Republic of Korea
  5. 5Beckman Laser Institute Korea, Dankook University College of Medicine, Chonan, Republic of Korea
  6. 6Division of Allergy-Immunology, Department of Internal Medicine, University of South Florida College of Medicine, Tampa, Florida, USA
  7. 7Department of Biostatistics, Boramae Medical Center, Seoul, Republic of Korea
  1. Correspondence to Dae Woo Kim, Department of Otorhinolaryngology-Head and Neck Surgery, Boramae Medical Center, Seoul National University College of Medicine, 425 Shindaebang 2-dong, Dongjak-gu, Seoul 156-707, Korea; kicubi{at}daum.net

Abstract

Rationale Interleukin (IL)-33, a new member of the IL-1 family, is constitutively expressed in epithelial tissues and lymphoid organs and plays an important role in the pathogenesis of allergic disease. However, the role of IL-33 in chronic rhinosinusitis with nasal polyps (CRSwNP) remains unclear.

Objective To investigate the role of IL-33 in the pathophysiology of CRSwNP.

Methods We investigated IL-33 expression and its cellular origins in the nasal polyps (NPs) of human subjects by immunohistochemistry (IHC), quantitative reverse transcription PCR (qRT-PCR), and multiplex cytokine assays. Correlations between IL-33 expression and other inflammatory markers were also explored. To investigate the role of IL-33 in CRSwNP, anti-IL-33 antibody was used in a murine model of CRS.

Results Uncinate process tissues from control (19), CRSsNP (61), CRSwNP (69) and NP tissues (71) were used in this study. Increased expression of IL-33 mRNA and protein in patients with CRSwNP compared with controls was observed. The concentration of IL-33 protein in CRSwNP was positively correlated with the number of neutrophils and the expression of several Th1 and Th17 inflammatory markers, including interferon (IFN)-γ, IL-1β, tumour necrosis factor (TNF)-α, IL-17A, IL-22, and various markers for neutrophil recruitment. However, protein levels of IL-5 and quantity of eosinophils were inversely correlated with levels of IL-33. The expression of tissue inhibitor of metalloproteinase (TIMP)-1 was negatively correlated with IL-33 protein levels, while the expression of matrix metalloproteinase (MMP)-2 and MMP-9 was positively correlated with IL-33 protein levels. In animal studies, IL-33 expression was upregulated in the CRSwNP group compared with controls. Anti-IL-33 treatment reduced the thickness of oedematous mucosa, subepithelial collagen deposition, and infiltration of neutrophils, but infiltration of eosinophils was not reduced. This treatment also inhibited the expression of neutrophilic inflammatory cytokines, but not IL-4. In addition, the expression of intracellular adhesion molecule 1, vascular adhesion molecule 1 and CXCL-2 in the nasal mucosa was suppressed in mice treated with anti-IL-33 antibody.

Conclusions Our data suggest a role for IL-33 in the pathogenesis of CRSwNP via neutrophil recruitment. Therefore, anti-IL-33 may provide a new treatment strategy to target infiltrating neutrophils in CRSwNP.

  • Airway Epithelium
  • Neutrophil Biology

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Footnotes

  • Contributors Study supervision: DWK. Critical revision of the manuscript for important intellectual content: D-KK, HRJ and KME. Conceived and designed the experiments: D-KK and DWK. Performed the experiments and analysed the data: D-KK, J-HM, SHC, SO and DWK. Contributed reagents/materials/analysis tools and wrote the paper: D-KK, DC and DWK.

  • Funding This research was supported by a clinical research grant-in-aid from the Seoul Metropolitan Government Seoul National University (SMG-SNU) Boramae Medical Center (03-2013-7), by SK Telecom Research Fund (01-2014-10).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval This study was approved by the institutional review board of Seoul National University (Boramae Medical Center).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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