Agree to disagree: The contradiction between IL-18 and IL-37 reveals shared targets in cancer

• Published in: Pharmacological research 2024-02, Vol.200, p.107072-107072, Article 107072
• Main Authors: Wang, Dongjie, Zhang, Bitian, Liu, Xiaolin, Kan, Lea Ling-Yu, Leung, Ping-Chung, Wong, Chun-Kwok
• Format: Article
• Language: English
• Subjects: Cancer; Cytokines; Humans; IL-18; IL-37; Inflammation; Interleukin-18 - metabolism; Neoplasms; Signal Transduction
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2024.107072

IL-37 is a newly discovered member of the IL-1 cytokine family which plays an important role in regulating inflammation and maintaining physiological homeostasis. IL-37 showed a close relationship with IL-18, another key cytokine in inflammation regulation and cancer development. IL-37 affects the function of IL-18 either by binding to IL-18Rα, a key subunit of both IL-37 and IL-18 receptor, or by drastically neutralizing the IL-18 protein expression of IL-18 binding protein, an important natural inhibitory molecule of IL-18. Moreover, as another subunit receptor of IL-37, IL-1R8 can suppress IL-18Rα expression, functioning as a surveillance mechanism to prevent overactivation of both IL-18 and IL-37 signaling pathways. While IL-18 and IL-37 share the same receptor subunit, IL-18 would in turn interfere with IL-37 signal transduction by binding to IL-18Rα. It is also reported that IL-18 and IL-37 demonstrated opposing effects in a variety of cancers, such as glioblastoma, lung cancer, leukemia, and hepatocellular cancer. Although the mutual regulation of IL-18 and IL-37 and their diametrically opposed effects in cancers has been reported, IL-18 has not been taken into consideration when interpreting clinical findings and conducting mechanism investigations related to IL-37 in cancer. We aim to review the recent progress in IL-18 and IL-37 research in cancer and summarize the correlation between IL-18 and IL-37 in cancer based on their expression level and underlying mechanisms, which would provide new insights into elucidating the conflicting roles of IL-18 and IL-37 in cancer and bring new ideas for translational research related to IL-18 and IL-37. [Display omitted]