Interleukin 18 (IL18) was originally identified as an inflammation-induced cytokine that is secreted by immune cells. An increasing number of studies have focused on its non-immunological functions, with demonstrated functions for IL18 in energy homeostasis and neural stability. IL18 is reportedly required for lipid metabolism in the liver and brown adipose tissue. Furthermore, IL18 (Il18) deficiency in mice leads to mitochondrial dysfunction in hippocampal cells, resulting in depressive-like symptoms and cognitive impairment. Microarray analyses of Il18^−/− mice have revealed a set of genes with differential expression in liver, brown adipose tissue, and brain; however, the impact of IL18 deficiency in these tissues remains uncertain. In this review article, we discuss these genes, with a focus on their relationships with the phenotypic disease traits of Il18^−/− mice.

Interleukin-18 (IL18) is an inflammatory cytokine that is related to psychiatric disorders such as depression and cognitive impairment. We previously found that IL18 deficiency may cause hippocampal impairment, resulting in depression-like behavioral changes. However, the potential role of IL18 in stressful conditions remains uncertain. In the present study, we examined the effect of IL18 on neural inflammation and stress tolerance during acute stress. Littermate Il18^+/+ and Il18^−/− mice were exposed to a single restraint stress for 6 h, and all assessments were performed 18 h after the mice were released from the restraint. In Il18^−/− mice exposed to acute stress, the immobility times in both the forced swim test and tail suspension test were decreased, although no difference was observed in Il18^+/+ mice. Il1β, Il6, and Tnfα expression levels in the hippocampus of stressed Il18^−/− mice were significantly higher than those in the other groups. Moreover, the numbers of astrocytes and microglia, including those in the active form, were also increased compared with those in other groups. Regarding the molecular mechanism, the HSF5 and TTR genes were specifically expressed in stressed Il18^−/− mice. As a potential treatment, intracerebral administration of IL18 to Il18^−/− mice resulted in partial recovery of changes in behavioral assessments. Our results revealed that IL18-deficient mice were more sensitive and had a longer response to acute stress than that in normal mice. In addition, neural inflammation and augmentation of glucocorticoid signals caused by stress were more intense and remained longer in Il18^−/− mice, resulting in behavioral changes. In conclusion, IL18 might be an indispensable factor that modulates the stress response and maintains balance between neural inflammation and glucocorticoid signaling.

The cytokine, interleukin-18 (IL-18), was originally identified as an interferon-γ-inducing proinflammatory factor; however, there is increasing evidence suggesting that it has non-immunological effects on physiological functions. We have previously investigated the potential pathophysiological relationship between IL-18 and dyslipidemia, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, which were mediated by lipid energy imbalance. Therefore, herein we focused on brown adipocytes (BAs) and brown adipose tissue (BAT) related to energy consumption as non-shivering thermogenesis. Il18−/− male mice were generated on the C57Bl/6 background, and littermate C57Bl/6 Il18+/+ male mice were used as controls. To reveal the direct effect of IL-18, primary cell cultures derived from both mice were established. Moreover, for molecular analysis, microarray, quantitative reverse transcription PCR and western blotting were performed using 6 and 12 weeks old mice. To evaluate the short- and long-term effects of IL-18 on BAT, recombinant IL-18 was administered for 2 and 12 weeks, respectively. Compared with Il18+/+ mice, BAT of Il18−/− mice showed earlier differentiation and lipid accumulation. To examine the direct effect of IL-18 on BAT, BA cell cultures were established. Myogenic factor 5-expressing adipose precursor cells were extracted from Il18+/+ and Il18−/− mice. PR domain containing 16 (PRDM16), a differentiation inducer, was strongly expressed in Il18−/− BAs, and uncoupling protein 1, a thermogenic and differentiation marker, was upregulated, resulting in the promotion of BA differentiation. Moreover, PRDM16-dependent and independent molecules related to BAT function, such as fibroblast growth factor 21, were activated. These findings were confirmed by comparing Il18+/+ and Il18−/− mice at 6 and 12 weeks of age. Additional analyses of the molecular mechanisms influencing the ‘Quantity of adipocytes’ identified three associated genes, apolipoprotein C3 (Apoc3), insulin-induced gene 1 (Insig1) and vitamin D (1,25-dihydroxyvitamin D3) receptor (Vdr). Intravenous administration of IL-18 not only significantly improved the expression of some of these genes, but it also significantly decreased the adipocytes’ size. This study demonstrated the critical function of IL-18 in differentiation and lipid metabolism in BAs. Furthermore, IL-18 may contribute to novel treatments by improving the energy imbalance.

Interleukin‐18 (IL‐18) is an inflammatory cytokine that has been linked to energy homeostasis and psychiatric symptoms such as depression and cognitive impairment. We previously revealed that deficiency in IL‐18 led to hippocampal abnormalities and resulted in depression‐like symptoms. However, the impact of IL‐18 deficiency on other brain regions remains to be clarified. In this study, we first sought to confirm that IL‐18 expression in neural cells can be found in human brain tissue. Subsequently, we examined the expression of genes in the prefrontal cortex of Il18^−/− mice and compared it with gene expression in mice subjected to a chronic mild stress model of depression. Extracted genes were further analyzed using Ingenuity® Pathway Analysis, in which 18 genes common to both the chronic mild stressed model and Il18^−/− mice were identified. Of those, 16 were significantly differentially expressed between Il18^+/+ and Il18^−/− mice. We additionally measured protein expression of α‐2‐HS‐glycoprotein (AHSG) and transthyretin (TTR) in serum and the brain. In the prefrontal cortex of Il18^−/− mice, TTR but not AHSG was significantly decreased. Conversely, in the serum of Il18^−/− mice, AHSG was significantly increased but not TTR. Therefore, our results suggest that in IL‐18‐deficit conditions, TTR in the brain is one of the mediators causally related to depression, and AHSG in peripheral organs is one of the regulators inducing energy imbalance. Moreover, this study suggests a possible “signpost” to clarify the molecular mechanisms commonly underlying the immune system, energy metabolism, neural function, and depressive disorders.

Interleukin (IL)‑18 is an interferon γ‑inducing inflammatory cytokine associated with function of the immune system and other physiological functions. IL‑18‑deficient (Il18‑/‑) mice exhibit obesity, dyslipidemia, non‑alcoholic steatohepatitis and depressive‑like behavioral changes. Therefore, IL‑18 has a number of important roles associated with immunity, energy homeostasis and psychiatric conditions. In the present study, gene expression in the brains of Il18‑/‑ mice was analyzed to identify genes associated with the depressive‑like behaviors and other impairments displayed by Il18‑/‑ mice. Using whole genome microarray analysis, gene expression patterns in the brains of Il18+/+ and Il18‑/‑ mice at 6 and 12 weeks of age were examined and compared. Subsequently, genes were categorized using Ingenuity® Pathway Analysis (IPA). At 12 weeks of age, 2,805 genes were identified using microarray analysis. Genes related to ‘Major depression’ and ‘Depressive disorders’ were identified by IPA core analysis, and 13 genes associated with depression were isolated. Among these genes, fibroblast growth factor receptor 1 (Fgfr1); protein tyrosine phosphatase, non‑receptor type 1 (Ptpn1); and urocortin 3 (Ucn3) were classed as depression‑inducing and the other genes were considered depression‑suppressing genes. Subsequently, the interactions between the microarray results at 6 weeks of age and the above three depression‑inducing genes were analyzed to search for effector genes of depression at 12 weeks of age. This analysis identified cyclin D1 (Ccnd1) and NADPH oxidase 4 (Nox4). The microarray analysis results were correlated with the results of reverse transcription-quantitative PCR (RT-qPCR). Overall, the results suggest that Fgfr1, Ptpn1 and Ucn3 may be involved in depression‑like changes and Ccnd1 and Nox4 regulate these three genes in IL‑18‑deficient mice.