The stress and the alarmin-like cytokine interleukin-37 mediated extracellular and intracellular signal pathways

IL-37, as a member of the IL-1 cytokine family, has been extensively characterized as a critical immunoregulatory molecule that suppresses both innate and adaptive immune responses. This cytokine demonstrates constitutive and inducible expression patterns across various immune and non-immune cells in response to diverse extracellular stimuli. Among its five identified isoforms (a, b, c, d, and e), IL-37b remains the most comprehensively studied variant. Compelling experimental evidence from murine models demonstrates that IL-37b exerts protective effects across a spectrum of pathological conditions, including inflammatory disorders, autoimmune diseases, neoplastic processes, and Alzheimer's disease (AD). In human, IL-37 serves as a natural modulator of inflammatory cascades with clinical studies frequently documenting dysregulated expression levels in patients with chronic inflammatory and autoimmune conditions. The anti-inflammatory mechanisms of IL-37b are primarily mediated through dual pathways: 1) extracellular signaling via the IL-18Rα receptor complex, and 2) intracellular modulation through direct interaction with signaling molecules such as Smad3. Recent advancements from our research group and others have elucidated novel biological functions for IL-37d and IL-37a isoforms and identified previously unrecognized intracellular targets of IL-37 including RAC1, C/EBPβ, and Rheb. This comprehensive review systematically examines current advancements in understanding IL-37's biological functions, with particular emphasis on emerging insights into its intracellular mechanisms of action in stress-associated pathologies.