IL33, a cytokine belonging to the IL-1 family, is constitutively produced from structural and lining cells like fibroblasts, endothelial and epithelial cells [1,3,5]. Different from most cytokines, it is a nuclear cytokine passively released during cell necrosis or tissue damage, acting as an alarmin to alert the immune system [1,5]. It plays key roles in type-2 innate immunity by activating various immune cells such as eosinophils, basophils, mast cells, macrophages, and group 2 innate lymphoid cells (ILC2s) through its receptor ST2 [1,5]. The IL33/ST2 axis is also involved in many inflammatory, infectious, and autoimmune diseases [3]. Genetic models, especially knockout (KO) mouse models, are valuable for studying its functions.

In mouse models of spontaneous breast cancer metastasis, targeting IL33 in vivo inhibited lung metastasis and attenuated immune cell recruitment and type 2 immunity, suggesting its role in facilitating breast cancer lung metastasis by modifying the immune microenvironment [2]. In pancreatic cancer, using compartment-specific IL33 knockout mice, lack of stromal IL33 led to reprogramming of the pancreatic tumor microenvironment, increased CD8+ T-cell infiltration and activation, and reduced tumor growth, indicating IL33's role in promoting tumor growth by directing the pancreatic microenvironment [4].

In conclusion, IL33 is a crucial immune modulator with pleiotropic activities in various immune responses and plays important roles in allergic, fibrotic, infectious, and chronic inflammatory diseases as well as in cancer metastasis and growth. The use of IL33 KO mouse models has revealed its specific functions in breast and pancreatic cancer, contributing to our understanding of these disease mechanisms.

References:

1. Chan, Ben C L, Lam, Christopher W K, Tam, Lai-Shan, Wong, Chun K. 2019. IL33: Roles in Allergic Inflammation and Therapeutic Perspectives. In Frontiers in immunology, 10, 364. doi:10.3389/fimmu.2019.00364. https://pubmed.ncbi.nlm.nih.gov/30886621/

2. Shani, Ophir, Vorobyov, Tatiana, Monteran, Lea, Barshack, Iris, Erez, Neta. 2020. Fibroblast-Derived IL33 Facilitates Breast Cancer Metastasis by Modifying the Immune Microenvironment and Driving Type 2 Immunity. In Cancer research, 80, 5317-5329. doi:10.1158/0008-5472.CAN-20-2116. https://pubmed.ncbi.nlm.nih.gov/33023944/

3. Tonacci, Alessandro, Quattrocchi, Paolina, Gangemi, Sebastiano. 2019. IL33/ST2 Axis in Diabetic Kidney Disease: A Literature Review. In Medicina (Kaunas, Lithuania), 55, . doi:10.3390/medicina55020050. https://pubmed.ncbi.nlm.nih.gov/30769901/

4. Donahue, Katelyn L, Watkoske, Hannah R, Kadiyala, Padma, Zhang, Yaqing, Pasca di Magliano, Marina. . Oncogenic KRAS-Dependent Stromal Interleukin-33 Directs the Pancreatic Microenvironment to Promote Tumor Growth. In Cancer discovery, 14, 1964-1989. doi:10.1158/2159-8290.CD-24-0100. https://pubmed.ncbi.nlm.nih.gov/38958646/

5. Cayrol, Corinne, Girard, Jean-Philippe. . Interleukin-33 (IL-33): A nuclear cytokine from the IL-1 family. In Immunological reviews, 281, 154-168. doi:10.1111/imr.12619. https://pubmed.ncbi.nlm.nih.gov/29247993/