IL25, also known as IL17E, is a unique cytokine of the IL-17 family. It is a key regulator of type 2 immunity, strongly inducing cytokines associated with this immune response. It is produced by various immune cells and a large amount comes from epithelial cells. IL25 is involved in maintaining tissue homeostasis and is associated with the Hedgehog signaling pathway among others [2]. Genetic models, especially KO/CKO mouse models, have been crucial in understanding its functions.

Genetic deletion of IL25 in AOM/DSS-treated mice inhibited tumor formation and growth in the context of colitis-associated tumorigenesis, prolonged survival, and revealed its role in promoting cancer stem cell properties via the Hedgehog pathway [1]. In an Apc mutation-driven model of spontaneous intestinal tumorigenesis, ablation of IL25 signaling reduced tumors and doubled life expectancy, as IL25 promoted an innate cancer-permissive microenvironment by activating ILC2s which sustained MDSCs to suppress antitumor immunity [4]. In IL17RB+ breast cancer mouse models, IL25+ macrophages promoted tumor progression, and blocking IL25 in combination with CDK4/6 inhibitors improved anti-tumor efficacy [3].

In conclusion, IL25 plays essential roles in type 2 immunity and tissue homeostasis. Through KO/CKO mouse models, its significance in cancer-related processes such as colitis-associated tumorigenesis, Apc mutation-driven intestinal tumorigenesis, and IL17RB+ breast cancer has been revealed. These findings highlight IL25 as a potential prognostic factor and therapeutic target in certain cancers.

References:

1. Liu, Junxi, Qian, Bingxiu, Zhou, Lin, Gao, Guoquan, Yang, Zhonghan. 2022. IL25 Enhanced Colitis-Associated Tumorigenesis in Mice by Upregulating Transcription Factor GLI1. In Frontiers in immunology, 13, 837262. doi:10.3389/fimmu.2022.837262. https://pubmed.ncbi.nlm.nih.gov/35359953/

2. Borowczyk, Julia, Shutova, Maria, Brembilla, Nicolo Costantino, Boehncke, Wolf-Henning. 2021. IL-25 (IL-17E) in epithelial immunology and pathophysiology. In The Journal of allergy and clinical immunology, 148, 40-52. doi:10.1016/j.jaci.2020.12.628. https://pubmed.ncbi.nlm.nih.gov/33485651/

3. Ozaki, Yukinori, Kinowaki, Keiichi, Kawabata, Hidetaka, Kudo-Saito, Chie. 2023. IL25+ macrophages are a key determinant of treatment resistance of IL17RB+ breast cancer. In American journal of cancer research, 13, 4931-4943. doi:. https://pubmed.ncbi.nlm.nih.gov/37970362/

4. Jou, Eric, Rodriguez-Rodriguez, Noe, Ferreira, Ana-Carolina F, Buczacki, Simon J A, McKenzie, Andrew N J. 2022. An innate IL-25-ILC2-MDSC axis creates a cancer-permissive microenvironment for Apc mutation-driven intestinal tumorigenesis. In Science immunology, 7, eabn0175. doi:10.1126/sciimmunol.abn0175. https://pubmed.ncbi.nlm.nih.gov/35658010/