Inflammasome-Mediated Cytokines: A Key Connection between Obesity-Associated NASH and Liver Cancer Progression

Figures

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  Figure 1. Inflammasomes-mediated cytokines IL-1β and IL-18 in liver cancer progression. In the liver, IL-1β leads to the release of IL-6 and TNF-α, cytokines related to a worse prognosis in hepatocellular carcinoma (HCC). IL-1β binds to interleukin-1 receptor type I (IL-1RI) and, after a series of cascades, activates nuclear factor kappa B (NF-κB), which in turn is related to proliferation and inflammation. IL-1β is also capable of promoting the expression of an oncoprotein, Gankyrin, which plays a critical role in HCC development and metastasis. M1 macrophages induce the expression of programmed death ligand 1 (PD-L1) in HCC cells through IL-1β, supporting the pro-tumor role of M1 macrophages and IL-1β. IL-18 receptor (rIL-18) is capable of increasing NF-κB activation and anti-apoptotic molecule expression, including Bcl-xL and xIAP. IL-18 can also regulate Th17 cells, which can both worsen prognosis or affect antitumor cytotoxicity by CD8+ T-cells. Finally, IL-18 could inhibit HBV replication but could also promote hepatocyte cell metastasis and migration.

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  Figure 2. Impact of IL-1β and IL-18 from obesity, dysbiosis, and non-alcoholic steatohepatitis (NASH) in hepatocellular carcinoma (HCC) progression. Insulin resistance (IR) from obesity increases lipolysis, which leads to liver lipid storage and contributes to NASH establishment. LDL (low-density lipoprotein) and cholesterol from obesity can activate NLRP3 inflammasome, contributing to NASH development and resulting in IL-1β release. IL-18 is also released in the obesity state. Dysbiosis is known to occur in obese individuals with dysregulation in NLRP6 inflammasome and consequent IL-1β and IL-18 releasing. IL-1β can modulate hepatic stellate cells (HSCs), resulting in the progression from liver injury to fibrogenesis, which contributes to HCC development and supports epithelial-mesenchymal transition in HCC cells through IL-1β/HIF-1α/COX2 axis in hypoxic conditions. In turn, the role of IL-18 in NASH, and consequently in HCC progression, is controversial in the literature (the symbol “?” indicates the uncertain role of IL-18 in HCC progression). This inflammatory environment supported by IL-1β and IL-18 from obesity, dysbiosis, and NASH promotes an increase in cells with genetic…

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  Figure 3. Inhibition of IL-1β and IL-18 and its consequences in hepatocellular carcinoma (HCC) growth. Inhibition of IL-1β results in the inhibition of pathways affected by this cytokine, such as nuclear factor kappa B (NF-κB), which possibly results in the inhibition of tumor growth. Inhibition of IL-18 appears to have dual consequences, either reducing HCC growth or favoring poor prognosis by impairing tumor-infiltration T CD8+ cells.