Expression and Clinical Significance of IL-33 and IL-25 in Post-Irradiation Otitis Media with Effusion

Zhihe Lin,1,* Chuntao Deng,2,* Dan Wang,3,* Bo Lyu,1 Jiaying Pan,4 Jinlian Li,1 Minting Chen,1 Zhaoxia Zhang,5 Zibin Liang,6 Lei Chen,7 Shaoyan Feng1 1Department of Otolaryngology, Head and Neck Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China; 2Department of Radiation Oncology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China; 3Department of Gastrointestinal Surgery, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China; 4Department of Otolaryngology, Eye and ENT Hospital, ENT Institute, Fudan University, Zhuhai, Guangdong, People’s Republic of China; 5Office of Organ Transplant Management, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China; 6Department of Thoracic Oncology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China; 7Department of Neurosurgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shaoyan Feng, Email [email protected]; [email protected] Lei Chen, Email [email protected]: This study investigates IL-33 and IL-25 expression in post-radiation otitis media with effusion (POME), along with classic oxidative stress markers (MDA and SOD), to investigate radiation-induced oxidative stress and its association with ILC2-mediated chronic inflammation, providing basis for targeted therapies.Methods: Middle ear effusions (MEE) were collected from 35 irradiated nasopharyngeal carcinoma patients with otitis media with effusion (POME, 43 ears) and 20 non-irradiated conventional chronic otitis media with effusion (CCOME, 20 ears) patients. IL-33, IL-25, IL-6, SOD, and MDA levels were measured by ELISA. Eustachian tube function was evaluated using the Endoscopic Evaluation of the Eustachian Tube (3ET) scoring system.Results: Comparative analysis revealed distinct molecular profiles between POME and CCOME, with POME showing significantly reduced IL-33 levels (p=0.046) but elevated SOD activity (p=0.015), along with a non-significant trend toward higher MDA (p=0.083). Temporal analysis demonstrated peak expression of both IL-25 and IL-33 at 6 months post-radiation. Correlation studies identified significant associations between IL-33 (r=0.391) and IL-6, as well as between IL-25 (r=0.483) and IL-6 (both p< 0.01). Clinically, IL-25 levels showed positive correlation with 3ET endoscopic scores (r=0.407, p=0.021) and were significantly reduced following tympanostomy tube placement (p=0.024). Notably, no direct correlation was observed between IL-33 and IL-25 (p> 0.05), nor were any significant associations found with allergic comorbidities (all p> 0.05).Conclusion: IL-33 and IL-25 synergistically drive ILC2-mediated chronic inflammation in radiation-induced OME, with IL-25 emerging as a biomarker for radiotherapy-associated Eustachian tube dysfunction. The 6-month cytokine surge post-radiation highlights a therapeutic window for targeted interventions to mitigate long-term complications. Keywords: post-irradiation, otitis media with effusion, nasopharyngeal carcinoma, interleukin-33, interleukin-25