IL-1β Signaling Complexity and Immune System Implications

The pro-inflammatory cytokine interleukin-1 beta (IL-1β) is essential for controlling the immune system and the inflammatory response. Pro-IL-1β is the precursor protein that is created throughout its maturation by the intracellular signaling complexes known as inflammasomes. ^[1]
Different cell types, such as macrophages, monocytes, and dendritic cells, all release IL-1β in response to an infection, an injury, or other types of cellular stress. When activated, these cells release IL-1β into the extracellular space, where it binds to target cells' receptors and starts signaling cascades. ^[2]
Many cell types, including immune cells like neutrophils, macrophages, and T cells as well as non-immune cells including chondrocytes, synoviocytes, and endothelial cells, can be impacted by IL-1β. Inflammatory mediators are produced, and immune responses are activated when IL-1β binds to its receptors on these cells and starts the subsequent signaling pathways. Depending on the environment and the presence of other cytokines or immune modulators, the specific effects of IL-1β on various cell types may change.
Depending on the situation, IL-1β has been discovered to have pro- and anti-tumor effects. When IL-1β is present, it may encourage angiogenesis and the activation of NF-κB signaling pathways, which may in turn increase tumor growth. On the other hand, it has also been demonstrated that IL-1β exerts anti-tumor effects by causing tumor cells to undergo apoptosis and triggering immunological responses against malignancies. As a result, modulation of IL-1β signaling presents a potential therapeutic strategy for the treatment of these conditions. ^{[3, 4]}     


   
 

How does IL-1β be used in cell therapy?


IL-1β has been shown to play a role in the induction of antitumor Th9 cells, which are a type of CD4⁺ T cell that produce IL-9 and have been implicated in the immune response against cancer.
According to earlier research, naive T cells can develop into Th9 cells in the presence of IL-4 and TGF-β. ^[5] However, in these few years, IL-1β is shown to be a better alternative to TGF-β for the differentiation of Th9 cells, which have potent antitumor capabilities. The combination of IL-1β and IL-4 effectively increased IL-9-producing T cells when TGF-β was substituted by IL-1β. Th9^IL-4+IL-1β cells, in contrast to the classic Th9^IL-4+TGF-β cells, display a less fatigued state, manifest a gene signature associated with cytotoxic T effector cells, exhibit more efficient tumor-killing abilities, and induce a more effective antitumor response in a melanoma murine model. ^[6]
Lots of studies have shown that Th9 cells play an important role in the immune response against cancer, by enhancing the recruitment and activation of other immune cells, such as CD8+ T cells, natural killer (NK) cells, natural killer T (NKT) cells, and by directly inhibiting the growth and proliferation of cancer cells. Therefore, IL-1β may be a potential target for the development of immunotherapies that enhance the antitumor activity of Th9 cells. ^[7]

There is one more study that shows that IL-1β can help Th9 cells to differentiate in situations where there is not enough IL-2. This is because IL-1β can make Th9 cells more sensitive to low levels of IL-2, which is necessary for Th9 cell differentiation. IL-1β achieves this by suppressing the activity of a protein called BCL6, which normally inhibits Th9 cell differentiation. Compared to other factors that activate a protein called NF-kB, IL-1β is the only one that can rescue Th9 differentiation in IL-2-limited conditions. ^[8]






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