Abstract
The human Interleukin-33 (IL-33), a member of the IL-1 family, is the cytokine as a cell endogenous alarmin, released by damaged or necrotic barrier cells (endothelial and epithelial cells). The signal transduction of IL-33 relies on recognition and interaction with specific receptor ST2, mainly expressed in immune cells. In both innate and adoptive immunity, IL-33 regulates the homeostasis in response to stress from within/out the microenvironment. Various, even negative biofunctions of IL-33 pathways have now been widely verified in pathogenesis among immunological mechanisms, like Th2-related immune-stimuli, inflammation/infection-induced tissue protectors. A larger versatility in studies of IL-33 on malignancies now focuses on: (1) promoting myeloid-derived suppressor cells (MDSC), (2) intervention toward CD8+ T, Natural Killer (NK) cell infiltration, group 2 innate lymphoid cells (ILC2) proliferation, dendritic cells (DC) activation, and (3) inhibiting tumor growth and/or further metastasis as an immunoadjuvant. Although IL-33 functioned pro-tumorigenically in various cancers, for some cancer types the findings so far are controversial. This review begins from a summarized introduction of IL-33, to its remarkable implications and molecular transduction pathway in malignant neoplasms, ends with latest inspiration for IL-33 in treatment.
Highlights
Cytokines are central mediators between cells in the inflammatory tumor microenvironment, in which Interleukin-33 (IL-33) is considered as an alarmin released after cellular damage
IL-33 is rapidly released from cells during necrosis or tissue injury, and signals through a cell surface receptor complex, ST2 (IL-1 receptor-like 1, IL1RL1) and IL1RAcP (IL-1 receptor accessory protein), to initiate inflammatory pathways in immune cells, such as type-2 innate lymphoid cells (ILC2), mast cells and natural killer (NK) cells [6]
The type 1 immune response is a critical component of cell-mediated immunity, which includes tumorinduced IFN-γ-producing Th1 cells, cytotoxic T lymphocytes, Natural Killer (NK) T cells, and γδ T cells, to limit tumor growth and metastasis [14]
Summary
Cytokines are central mediators between cells in the inflammatory tumor microenvironment, in which Interleukin-33 (IL-33) is considered as an alarmin released after cellular damage. The IL-1 gene family contains 11 members (IL-1α, IL-1β, IL-1RA, IL-18, IL-36RA, IL-36α, IL37, IL-36β, IL-36γ, IL-38, IL-33), which induces a complex network of pro-inflammatory cytokines, and regulates and initiates inflammatory responses, via expressing integrins on leukocytes and endothelial cells [1]. IL-33 is rapidly released from cells during necrosis or tissue injury, and signals through a cell surface receptor complex, ST2 (IL-1 receptor-like 1, IL1RL1) and IL1RAcP (IL-1 receptor accessory protein), to initiate inflammatory pathways in immune cells, such as type-2 innate lymphoid cells (ILC2), mast cells and natural killer (NK) cells [6]. Barrier structures with widespread of endothelial, epithelial and fibroblast-like cells that are exposed to the environment, were indicated high level of constitutive expression of IL-33. Related mechanism includes genomic instability and mutation, epigenetic modification, apoptosis resistance to cancer-initiated cells and increases of cancer metastasis
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