IL-25 as a novel therapeutic target in nasal polyps of patients with chronic rhinosinusitis.
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.


CONCLUSIONS
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.
Department of Pharmacology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea; Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Korea.
Hyun-Woo
HW
Shin
Department of Otorhinolaryngology, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon, Korea.
Dong-Kyu
DK
Kim
Department of Otorhinolaryngology-Head and Neck Surgery, Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea.
Min-Hyun
MH
Park
Department of Otorhinolaryngology-Head and Neck Surgery, Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea.
Kyoung Mi
KM
Eun
Department of Pharmacology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea.
Mingyu
M
Lee
Department of Pharmacology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea.
Daeho
D
So
Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Korea.
Il Gyu
IG
Kong
Department of Otorhinolaryngology, Dankook University College of Medicine, Chonan, Korea.
Ji-Hun
JH
Mo
Department of Internal Medicine, Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea.
Min-Suk
MS
Yang
Department of Otorhinolaryngology-Head and Neck Surgery, Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea.
Hong Ryul
HR
Jin
Department of Pharmacology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea.
Jong-Wan
JW
Park
Department of Otorhinolaryngology-Head and Neck Surgery, Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea. Electronic address: kicubi@daum.net.
Dae Woo
DW
Kim
D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology; D002908:Chronic Disease; D004195:Disease Models, Animal; D047150:Eosinophil Cationic Protein / Q000235:genetics / Q000276:immunology; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009298:Nasal Polyps / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000276:immunology; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000276:immunology; D012220:Rhinitis / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D012852:Sinusitis / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000276:immunology
D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C486701:IL25 protein, human; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D053722:Receptors, Interleukin-17; D020825:T-Box Domain Proteins; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D047150:Eosinophil Cationic Protein; C479220:RNASE3 protein, human
IL-25; Nasal polyp; allergy; animal models; sinusitis