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IL-18 is a proinflammatory and immune regulatory cytokine, member of the IL-1 family. IL-18 was initially identified as an IFN-γ-inducing factor in T and NK cells, involved in Th1 responses. IL-18 is produced as an inactive precursor (pro-IL-18) that is enzymatically processed into a mature form by Casp1. Different cells, such as macrophages, DCs, microglial cells, synovial fibroblasts, and epithelial cells, express pro-IL-18, and the production of bioactive IL-18 is mainly regulated at the processing level. PAMP or DAMP molecules activate inflammasomes, which trigger Casp1 activation and IL-18 conversion. The natural inhibitor IL-18BP , whose production is enhanced by IFN-γ and IL-27, further regulates IL-18 activity in the extracellular environment. Inflammasomes and IL-18 represent double-edged swords in cancer, as their activation may promote tumor development and progression or oppositely, enhance anti-tumor immunity and limit tumor growth. IL-18 has shown anti-tumor activity in different preclinical models of cancer immunotherapy through the activation of NK and/or T cell responses and has been tested in clinical studies in cancer patients. However, the dual role of IL-18 in different experimental tumor models and human cancers raises critical issues on its therapeutic use in cancer. This review will summarize the biology of the IL-18/IL-18R/IL-18BP system and will address the role of IL-18 and its inhibitor, IL-18BP, in cancer biology and immunotherapy., (© Society for Leukocyte Biology.)

Objective: The proinflammatory cytokine interleukin-18 (IL-18) putatively modulates food intake and energy metabolism, but the effects of IL-18 in high-fat diet fed animals are unknown. Whether IL-18 alters basal metabolic rate or metabolic processes of living is unknown. Here, we tested the hypothesis that IL-18 modulates weight gain, energy intake, whole-body energy expenditure, and utilization of lipid as a fuel substrate in high-fat diet fed mice., Methods: Food intake, whole-body metabolism, and motor activity of IL-18 knockout mice were compared to those of wildtype littermates; anorectic effects of intracerebroventricular IL-18 administration were compared between IL-18 receptor knockout, IL-18/IL-18R knockout and wildtype mice., Results: Chow-reared IL-18 knockout mice were overweight at 6 months of age and then gained excess weight on both low-fat and high-fat diets, ate more high-fat diet, and showed reduced whole-body energy expenditure and increased respiratory exchange ratios. Reductions in energy expenditure of IL-18 knockout mice were seen across fasting vs. feeding conditions, low- vs. high-fat diets, high vs. low levels of physical activity and times of day, suggesting actions on basal metabolic rate. The circadian amplitude of energy expenditure, but not respiratory exchange ratio, food intake, or motor activity, also was blunted in IL-18 knockout mice. Central IL-18 administration reduced high-fat diet intake in wildtype mice, but not in mice lacking the IL-18 receptor., Conclusion: The loss-of-function results support the hypothesis that endogenous IL-18 suppresses appetite and promote energy expenditure and lipid fuel substrate utilization not only during sickness, but also in healthy adults consuming high-fat diets., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To investigate the eutopic endometrial interleukin-18 (IL-18) system including interleukin-18 (IL-18), IL-18 receptor (IL-18R), and IL-18 binding protein (IL-18BP), mRNA, and protein expression in patients with adenomyosis., Design: A clinical and molecular study., Setting: Clinical and academic research setting in a university medical center., Patient(s): Twenty-eight samples of human eutopic endometria were obtained from surgical specimens of normal cycling women undergoing hysterectomy for uterine adenomyosis (n = 19); the control group (n = 9) was women undergoing hysterectomy for benign reason including uterine fibroids., Intervention(s): Quantitative competitive polymerase chain reaction (QC PCR) and immunohistochemistry studies were performed., Main Outcome Measurement(s): The differences of the IL-18 system mRNA and the ratio of IL-18BP to IL-18 in the eutopic endometrium of uterine adenomyosis and control group were analyzed., Result(s): IL-18 system mRNA and protein expression was demonstrated in the eutopic endometrium of both adenomyosis and control women. Quantitative competitive PCR demonstrated that endometrial IL-18R mRNA and the ratio of IL-18BP to IL-18 were significantly increased in adenomyosis patients in comparison to the control group. Pearson's correlation showed a significant correlation between IL-18 and IL-18R in the eutopic endometrium of women with uterine adenomyosis, but not the control group., Conclusion(s): The expression of the eutopic endometrial IL-18 system and the ratio of antagonist to agonist at the level of the endometrial-myometrial interface (EMI) may possibly be responsible for the pathologic process of adenomyosis., (Copyright (c) 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)