Interleukin-9 (IL-9) is a multifunctional cytokine. It is involved in various biological processes and diseases, and is transcriptionally regulated by non-coding regulatory elements surrounding the Il9 gene [4]. IL-9-producing CD4+ T helper 9 (Th9) cells are known to express the transcription factor PU.1, and IL-9 has been implicated in autoimmune diseases, cancer, and parasitic infections [1,2,5].

In rheumatoid arthritis (RA), the upregulation of IL-9 in patients shows a positive correlation with clinical markers. Using PU.1-T cell-conditional knockout (KO), IL-9 KO and IL-9R KO mice in collagen-antibody-induced arthritis (CAIA) and collagen-induced arthritis (CIA) models, interventions targeting PU.1 and IL-9 mitigated the inflammatory phenotype. Mechanistically, PU.1 and IL-9 form a positive feedback loop in RA [1]. In mast cells, deficiency of the mouse Il9 gene regulatory element (Il9 CNS-25) leads to decreased IL-9 production, reduced mast cell expansion in a food allergy model and decreased mast cell accumulation in a Nippostrongylus brasiliensis infection model [3]. In experimental cerebral malaria, neutralization of IL-9 along with IL-6 enhanced host survivability and modulated the Th17/Treg ratio [5].

In conclusion, IL-9 is crucial in multiple biological processes and diseases. Studies using KO and CKO mouse models have revealed its role in autoimmune diseases like RA, allergic diseases through mast cell regulation, and in modulating the immune response during parasitic infections such as experimental cerebral malaria. These models have provided valuable insights into IL-9's functions, potentially guiding the development of new therapeutic strategies for related diseases.

References:

1. Tu, Jiajie, Chen, Weile, Huang, Wei, Zhu, Chen, Wei, Wei. 2024. Positive feedback loop PU.1-IL9 in Th9 promotes rheumatoid arthritis development. In Annals of the rheumatic diseases, 83, 1707-1721. doi:10.1136/ard-2024-226067. https://pubmed.ncbi.nlm.nih.gov/39164066/

2. Do-Thi, Van Anh, Park, Sang Min, Park, Song Mi, Lee, Hayyoung, Lee, Jie-Oh. 2023. IL9 Polarizes Macrophages to M1 and Induces the Infiltration of Antitumor Immune Cells via MIP-1 and CXCR3 Chemokines. In Cancer research communications, 3, 80-96. doi:10.1158/2767-9764.CRC-22-0246. https://pubmed.ncbi.nlm.nih.gov/36968220/

3. Abdul Qayum, Amina, Koh, Byunghee, Martin, Rebecca K, Conrad, Daniel H, Kaplan, Mark H. 2019. The Il9 CNS-25 Regulatory Element Controls Mast Cell and Basophil IL-9 Production. In Journal of immunology (Baltimore, Md. : 1950), 203, 1111-1121. doi:10.4049/jimmunol.1900272. https://pubmed.ncbi.nlm.nih.gov/31350354/

4. Son, Aran, Baral, Ishita, Falduto, Guido H, Schwartz, Daniella M. 2024. Locus of (IL-9) control: IL9 epigenetic regulation in cellular function and human disease. In Experimental & molecular medicine, 56, 1331-1339. doi:10.1038/s12276-024-01241-y. https://pubmed.ncbi.nlm.nih.gov/38825637/

5. Ghosh, Soubhik, Mukherjee, Saikat, Sengupta, Anirban, Keswani, Tarun, Bhattacharyya, Arindam. 2022. CD4+IL9+ (Th9) cells as the major source of IL-9, potentially modulate Th17/Treg mediated host immune response during experimental cerebral malaria. In Molecular immunology, 152, 240-254. doi:10.1016/j.molimm.2022.11.005. https://pubmed.ncbi.nlm.nih.gov/36395532/