IL4I1, also known as Interleukin-4-induced gene 1, is a secreted L-phenylalanine oxidase [4]. It is mainly produced by inflammatory antigen-presenting cells, such as macrophages in T helper type 1 granulomas and various tumors. IL4I1 is involved in the fine control of B-and T-cell adaptive immune responses and plays a role in the tryptophan metabolic pathway [2,4]. Tryptophan catabolites generated by IL4I1 can activate the aryl hydrocarbon receptor (AHR), which is associated with tumor malignancy and suppression of anti-tumor immunity [1].

In preclinical models, IL4I1 has been shown to promote cancer cell motility, suppress adaptive immunity, and enhance the progression of chronic lymphocytic leukemia (CLL) in mice, indicating its role in cancer immune evasion [1]. In glioma, high IL4I1 expression in M2-like macrophages is associated with aggressive progression and poor prognosis, and it promotes the invasion and migration of glioma cells and the polarization of M2-like macrophages [3]. Also, IL4I1 in muscle stem cells can catalyze tryptophan metabolites to inhibit neutrophil infiltration and ameliorate acute lung injury in mice [5].

In conclusion, IL4I1 is a key enzyme in regulating immune responses and is involved in multiple biological processes, especially in the context of cancer and inflammation. Its role in promoting tumor progression in models like CLL and glioma suggests that targeting IL4I1 could be a potential strategy for cancer therapy. Additionally, its function in modulating inflammation in muscle-related models provides insights into its role in non-cancerous inflammatory conditions [1,3,5].

References:

1. Sadik, Ahmed, Somarribas Patterson, Luis F, Öztürk, Selcen, Seiffert, Martina, Opitz, Christiane A. 2020. IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression. In Cell, 182, 1252-1270.e34. doi:10.1016/j.cell.2020.07.038. https://pubmed.ncbi.nlm.nih.gov/32818467/

2. Zeitler, Leonie, Murray, Peter J. 2023. IL4i1 and IDO1: Oxidases that control a tryptophan metabolic nexus in cancer. In The Journal of biological chemistry, 299, 104827. doi:10.1016/j.jbc.2023.104827. https://pubmed.ncbi.nlm.nih.gov/37196768/

3. Ye, Feng, Wang, Lichong, Li, Yuanyou, Zhou, Liangxue, Xu, Jianguo. 2024. IL4I1 in M2-like macrophage promotes glioma progression and is a promising target for immunotherapy. In Frontiers in immunology, 14, 1338244. doi:10.3389/fimmu.2023.1338244. https://pubmed.ncbi.nlm.nih.gov/38250074/

4. Molinier-Frenkel, Valérie, Prévost-Blondel, Armelle, Castellano, Flavia. 2019. The IL4I1 Enzyme: A New Player in the Immunosuppressive Tumor Microenvironment. In Cells, 8, . doi:10.3390/cells8070757. https://pubmed.ncbi.nlm.nih.gov/31330829/

5. Zuo, Muqiu, Fang, Jiankai, Huang, Peiqing, Shi, Yufang, Shao, Changshun. 2023. IL4I1-catalyzed tryptophan metabolites mediate the anti-inflammatory function of cytokine-primed human muscle stem cells. In Cell death discovery, 9, 269. doi:10.1038/s41420-023-01568-x. https://pubmed.ncbi.nlm.nih.gov/37507432/