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Review

Molecular Mechanisms of IL18 in Disease

by
Kyosuke Yamanishi
1,2,*,
Masaki Hata
2,
Naomi Gamachi
2,
Yuko Watanabe
3,
Chiaki Yamanishi
3,
Haruki Okamura
2 and
Hisato Matsunaga
1,2
1
Department of Neuropsychiatry, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya 663-8501, Hyogo, Japan
2
Department of Psychoimmunology, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya 663-8501, Hyogo, Japan
3
Hirakata General Hospital for Developmental Disorders, Hirakata 573-0122, Osaka, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(24), 17170; https://doi.org/10.3390/ijms242417170
Submission received: 25 September 2023 / Revised: 30 November 2023 / Accepted: 3 December 2023 / Published: 6 December 2023
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
Browse Figure
Review Reports Versions Notes

Abstract

:
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.

1. Introduction

Interleukin (IL) 18 was initially cloned in 1995 and identified as a proinflammatory cytokine that stimulates type 1 helper T cells to produce interferon (IFN)-γ [1]. The 23-kDa precursor form of IL18 is activated by cleaved caspase-1 and secreted as an active, 18-kDa mature form [2,3,4,5,6]. IL18 is secreted by hematopoietic lineages, such as macrophage cells [1] and microglia [7], as well as non-immune cells such as neural cells [6]. IL18 plays multiple roles in immune function, energy metabolism, and psychiatric disorders [1,8,9,10,11], and is also a therapeutic target for cancer immunotherapy, inhibition of body weight gain, and cognitive impairment [8,10,12]. Furthermore, we previously reported the effectiveness of the combination of IL18 and immune checkpoint inhibitors in suppressing tumor metastasis [12]. IL18 may exert anti-metastatic effects by increasing the numbers of effector-like natural killer (NK) cells or decreasing immunosuppressive cells, such as regulatory T cells. While IL18 alone can prime lymphocytes, IL18 combined with IL2 can promote the proliferation of NK cells, resulting in increased cytotoxicity against cancer [13]. Moreover, the expansion and function of NK cells stimulated by IL15 and IL18 are controlled by IL12 [14]. Together, this leads to a mechanism whereby antigen-mediated activation of dendritic cells leads to the production of cleaved caspase-1 and release of active IL18 and IL2, induced proliferation of NK cells, and secretion of IFN-γ. Thus, IL18 is an essential cytokine in inflammatory responses and cancer immunotherapy.
Research has shown that IL18 is also closely associated with energy metabolism. In our studies on IL18-knockout (Il18−/−) mice, we observed a remarkable body weight gain over time in Il18−/− mice compared with wild-type littermate mice [8,15]. Furthermore, Il18−/− mice exhibited higher blood glucose and lipid levels, insulin resistance, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH) with aging. Regarding the mechanism of higher blood glucose levels and insulin resistance in Il18−/− mice, the phosphorylation of signal transducer and activator of transcription 3 (STAT3) was impaired in the liver and was recovered by the administration of recombinant-IL18 (rIL18) [15]. Additionally, Il18−/− mice with dyslipidemia, NAFLD, and NASH showed inhibition of the Wnt signaling pathway, reduced expression of cyclin D1 (Ccnd1), and disturbances in the circadian rhythm [8]. The dyslipidemia, NAFLD, and NASH in Il18−/− mice were improved by administration of rIL18. We performed an additional study on brown adipose tissue (BAT) in these mice and confirmed that IL18 deficiency had similar effects to those observed in the liver [9]. Nevertheless, the direct molecular role of IL18 in dyslipidemia, NAFLD, and NASH remains to be clarified.
IL18 also plays a role in psychiatric and neurologic conditions [10,16]. We reported that Il18−/− mice showed cognitive impairment and depressive-like behavioral changes compared with wild-type mice [10]. Another study on Il18−/− mice revealed degenerated mitochondria in presynaptic axon terminals of the molecular and polymorphic layer of hippocampal dentate gyrus, suggesting the possible dysfunction of neurotransmitter release [10]. These disruptions may be related to the mechanism underlying the observed cognitive impairment and behavioral changes in Il18−/− mice. Additionally, regulation of mitochondrial function may be involved in the role of IL18 in the brain. Furthermore, reports have identified several other genes, including transthyretin (Ttr), as having potential involvement in depression and cognitive impairment [10,17]. Therefore, the precise role and mechanisms of IL18 in brain dysfunction have not yet been clarified.
In this review, we summarize the current literature on genes showing differential expression (DEGs) between Il18−/− and wild-type mice, focusing on those categorized as being related to energy metabolism, psychiatric conditions, and the brain, and discuss the potential relationships of these DEGs with IL18-deficient phenotypes in mice. Considering the role of IL18 in cancer, we also discuss the current literature and potential mechanisms of differentially expressed cancer-related genes.

2. Microarray and Ingenuity Pathway Analysis (IPA)

In our previous studies, we obtained microarray data from the liver, BAT, and brain of Il18−/− mice at 12 weeks of age [8,9,10,17]. Genes with significantly increased or decreased expression compared with wild-type controls were extracted, and our analysis focused on DEGs that were commonly expressed in all three tissues (liver, BAT, and brain).
IPA was applied to analyze the functions of the DEGs, as previously described [18,19]. Of the tissue-specific DEGs, those associated with cancer, energy metabolism, and psychiatric and brain disorders (depression, dementia, Alzheimer’s disease [AD], and cognitive impairment) were selected on the basis of behaviors observed in Il18−/− mice [10]. The IPA network explorer was run with default settings to reveal molecule–molecule interactions and to detect pathways between the molecules.
The correlation between microarray and quantitative real-time PCR (RT-qPCR) results was analyzed using Spearman’s rank correlation tests. The rs and two-tailed p values for the microarray and RT-qPCR results of the liver, BAT, and brain were previously reported [8,9,17].
A diagram illustrating the interaction of the selected DEGs is provided in Figure 1.

3. IL18 and Cancer

An increasing number of studies have demonstrated a relationship between IL18 and cancer. In pancreatic ductal adenocarcinoma (PDA), serum and stromal IL18 is positively correlated with patient mortality [20,21]. High expression of IL18 in PDA was associated with worse disease progression and poor survival [22]. However, there is the other report that serum IL18 concentration was not correlated with patient survival of pancreatic adenocarcinoma [23]. In oral squamous cell carcinoma (OSCC), the serum levels of IL18 increase during tumor growth [24,25]. IL18 expression in peripheral blood mononuclear cells is also increased in OSCC patients compared with that in healthy individuals [25]. In OSCC patients with lymph node metastasis and a severe TNM stage, serum IL18 levels were significantly higher than those in patients without lymph node metastasis or a severe TNM stage. This trend has also been observed in patients with other cancers [25].
In clinical trials, systematic administration of IL18 significantly suppressed the growth of several kinds of carcinomas, such as melanoma and renal cell cancer, by stimulating the immune system [26,27,28]. Furthermore, we previously demonstrated the effectiveness of cancer immunotherapy using IL18 to augment immune checkpoint inhibitors [12]. Moreover, mutant IL18 engineered for resistance to inhibitory binding of the high-affinity IL-18 decoy receptor also promoted the activity of NK cells, resulting in the enhancement of anti-tumor effects in mouse tumor models [29]. These results suggest the possibility that IL18 may be an important cytokine in cancer treatment.

4. Cancer-Related Genes in Il18−/− Mice

Among the DEGs identified in our microarray analysis of Il18−/− mice, those with involvement in various cancers are listed in Table 1.
In human tongue squamous cell carcinoma cells, overexpression of IL18 led to apoptosis of tumor cells and decreased Ccnd1 expression [30]. Though Jihong et al. reported that Ccnd1 expression in the liver was unaffected by the administration of rIL18, they used BRL-3A rat liver cells to show that cell viability was increased with IL18 treatment [31]. In contrast, we found that IL18 administration increased the expression of Ccnd1 in the liver of wild-type and Il18−/− mice [8]. These results suggest that the IL18 receptor is expressed in the liver; however, the influence of IL18 on Ccnd1 may occur through an indirect mechanism.
Erdr1 is related to cancer and IL18 [32,33]. Increased expression of Erdr1 in mouse melanoma inhibited tumor growth and metastasis to the lung [32]. In another study, treatment with recombinant Erdr1 prevented invasion and migration of gastric cancer [34]. Overexpression of Erdr1 has also been shown to suppress the expression of Bcl2 and promote apoptosis [33,35,36]. Thus, Erdr1 plays a role in cell homeostasis. One study has shown that Erdr1 is negatively regulated by IL18 in melanoma cells [32]. Erdr1 and Nfkb regulate the activation of STAT3, which increases tumor progression [37,38]. We observed that STAT3 phosphorylation was impaired in the liver of Il18−/− mice, and was restored by r-IL18 treatment [15]. Erdr1 also functions as an immune activator that specifically activates NK cells [39]. Additionally, administration of recombinant ERDR1 augmented the cytotoxicity of primary human NK cells against leukemia cancer cells [39]. IL18 in combination with IL2 induces NK cells and has a cytotoxic role against cancers [13]. Consistent with other research [32], our microarray analysis showed that Erdr1 expression was increased in liver, BAT, and brain of Il18−/− mice, implying that Erdr1 and Il18 negatively regulate each other. We also reported decreased tumor sizes in lung metastasis models of melanoma treated with the combination of immune checkpoint inhibitors and IL18 [12]. Although Erdr1expression was not analyzed in our previous study, it is possible that the balance between Il18 and Erdr1 expression is important for the treatment of melanoma.
To the best of our knowledge, there are no previous reports on the relationship between Nxpe4 and IL18. In our microarray analysis, the expression of Nxpe4 was significantly decreased in all analyzed tissues. Colon cancer patients with decreased Nxpe4 expression were found to have high mortality [40], and Cygb-deficient mice with increased colon tumors also exhibited decreased Nxpe4 expression [41]. Therefore, future studies should examine whether Il18-/- mice with decreased Nxpe4 expression develop tumors over time.
Some reports have linked Nnmt and IL18 with cancer progression through the STAT3/IL1β pathway [42]. Our microarray analysis showed that the expression of Nnmt is significantly decreased in Il18−/− mice. In PC-3 cells, a prostate cancer cell line, Nnmt promoted cell viability, whereas knockdown of Nnmt in PC-3 cells decreased cell viability [43]. Further studies are required to understand the functional relationship between IL18 and Nnmt.
No studies have examined the relationship between Tmem25 and IL18. Only two studies have examined Tmem25 expression in colon and breast cancer [44,45]. One clinical study showed that Tmem25 expression was decreased in colorectal cancer; therefore, Tmem25 has been considered as a therapeutic target [46]. Reduced Tmem25 expression in breast cancer has been correlated with a better response to chemotherapy [44,45].
One study reported an association of Atm with IL18 [47]. In the colonic epithelium, the suppression of Atm reduces the activity of inflammasomes, including IL18, resulting in suppressed inflammation. In our microarray analysis of Il18−/− mice, the expression of Atm was also reduced. Taken together, these results indicate a positive correlation between the expression of Atm and that of Il18 [47]. Atm is reportedly a cancer risk factor [48,49]. One report showed that Atm variants and mutations are associated with the risk of pancreatic cancer [50,51]. Therefore, the relevance of the relationship between Atm and IL18 should be determined in further analyses.
No studies have examined the relationship between IL18 and Rps25. One clinical research study revealed that Rps25 expression was associated with the disease-specific survival rate in stage II mucinous colorectal cancer [52]. Furthermore, Rps25 is considered a potential biomarker in lung adenocarcinoma and T-cell leukemia [53,54]. In Il18−/− mice, the expression of Rps25 is decreased. Thus, further study is required to clarify the interaction between these two factors.
The potential association between Tmem267 with IL18 has also not been reported. One study showed a poor prognosis of liver and colon cancer in patients with elevated Tmem267 levels [55]. Increased expression of Tmem267 was also observed in Il18−/− mice. Therefore, Il18−/− mice may have a high risk of liver cancer.
The expression of Axin2 in Il18−/− mice was significantly decreased. Axin2 is a critical modulator of the Wnt/β-catenin signaling pathway [56]. The Axin2-Wnt pathway involves negative feedback regulation, and Axin2 is also a direct target of Wnt/β-catenin [56]. Axin2 is a known tumor suppressor gene in some cancers [57]. In contrast, several reports identified Axin2 as an oncogene in colorectal, liver, and gastric cancers [58]. Axin2 is a β-catenin target that is highly expressed in human colorectal cancer [59]. Another study showed that the Axin2 axis suppressed tumor growth and metastasis in colorectal cancer [60].
Caspase-4 (Casp4) is related to various malignancies and metastasis [61]. In non-small cell lung cancer (NSCLC) patients, the circulating Casp4 level was much higher than that in healthy individuals. Furthermore, increased levels of Casp4 in NSCLC patients led to higher mortality compared with those in NSCLC patients with low Casp4 gene levels [62]. In gastric cancer patients, high expression of Casp4 was associated with a better survival rate [63]. In esophageal squamous cell carcinoma, Casp4 may be a tumor suppressor gene [64]. Casp4 expression is decreased in Il18−/− mice. Therefore, tumor growth might be increased in Il18−/− mice compared with Il18+/+ mice.
Several reports have indicated the involvement of Chrm1 in both the promotion and inhibition of cancer growth. Chrm1 activates cholinergic signals and the hedgehog signaling pathway, resulting in the promotion of prostate cancer invasion [65,66]. Activation of Chrm1 also induced the migration and invasion of two cancer cell lines, HepG2 and SMMC-7721, via the PI3K/Akt pathway [67]. Signaling through Chrm1 inhibited primary pancreatic tumor growth via downregulation of the growth factor pathway [68]. In Il18−/− mice, Chrm1 expression was increased, indicating that tumor growth might be increased.
Ifi16 reportedly functions as both a tumor suppressor and a promoter. High expression of Ifi16 was observed in colorectal cancer [69,70]. Another study reported that Ifi16 promoted cancer development in vitro and in vivo [71]. Ifi16 protein also activates the STING-TBK1 pathway for IFN-β production [72]. Ifi16 functions as an activator of the inflammasome, resulting in the production of cleaved IL1β and IL18 [73]. One report showed that Ifi16 suppresses cell viability and increases apoptosis in hepatocellular carcinoma (HCC) cell lines [74]. In Il18−/− mice, the expression of Ifi16 is significantly decreased. Further study is required to determine whether IL18 suppresses or promotes cancer development through Ifi16.
Klf13 exhibits important functions in cell proliferation, migration, and differentiation [75,76]. Klf13 inhibits cell proliferation and accelerates apoptosis in pancreatic cancer cells [77], and functions as a tumor suppressor protein in prostate cancer and colorectal cancer [78,79]. Klf13 is also necessary for Ccnd1 expression, which is an oncogene in oral squamous cell carcinoma [80]. Klf13 and Fgfr3 are highly expressed in oral cancer cells [81]. In Il18−/− mice, the expression of Klf13 is significantly increased. Therefore, tumor proliferation might be promoted in Il18−/− mice.
Upregulated Lrrc8e led to cervical cancer cell proliferation and metastasis of breast cancer [82,83]. In Il18−/− mice, the expression of Lrrc8e is decreased. Lrrc8e and Il18 may be positively correlated; however, further study is warranted to determine whether IL18 can promote or suppress the growth of these tumor types.
In mouse models of cancer, LY6A has been identified as an important regulator of tumor progression [84,85,86]. LY6A exhibits marked influences on cellular activity and tumorigenicity, both in vitro and in vivo [87]. In Il18−/− mice, the expression of Ly6a is decreased. Further study is needed to determine whether IL18 suppresses or promotes cancer progression through Ly6a.
Nnt is overexpressed in gastric cancer. Nnt accelerates tumor growth, lung metastasis, and peritoneal dispersion of cancer [88]. Furthermore, Nnt expression is upregulated in adrenocortical carcinoma and triggers anti-apoptosis pathways in cancer cells [89]. In mouse models of lung tumor initiation and progression, the expression of Nnt significantly enhances tumor growth, invasion, and aggressiveness [90]. Expression of Nnt is increased in Il18−/− mice, indicating that tumor growth might be promoted.
Several previous studies have linked Samsn1 and cancer. The human SAMSN1 gene is located on chromosome 21q11-21, a region associated with heterozygous deletions frequently found in lung cancer cells, suggesting that SAMSN1 may be a tumor suppressor [91,92]. Additionally, SAMSN1 is a suppressive factor of multiple myeloma migration, both in vitro and in vivo [93]. Decreased expression of SAMSN1 may promote the progression and recurrence of gastric cancer [94]. High expression of Samsn1 was associated with high mortality in glioblastoma multiforme [95], but Samsn1 was found to be expressed at significantly low levels in HCC [96]. In Il18−/− mice, the expression of Samsn1 is significantly decreased, suggesting that tumor growth might be promoted.
There are no reports on the involvement of Npas1, Or10ad1, Ppcdc, or Wscd1 in cancer.

5. IL18 and Energy Metabolism

Previous studies have linked IL18 to energy metabolism, with potential roles in glucose and lipid homeostasis. High plasma levels of IL18 lead to a significant increase in the risk of type 2 diabetes (T2D), and serum levels of IL18 are significantly increased in patients with T2D compared with healthy controls [97,98,99]. Furthermore, IL18 levels in serum or plasma are negatively correlated with carbohydrate tolerance and positively related to insulin resistance [100,101,102]. High serum levels of IL18 increase the risk of metabolic syndrome characteristics such as hypertriglyceridemia, and are also linked to serum triglyceride levels [103,104]. In women with obesity, weight loss was found to reduce the levels of IL18 [105]. Plasma levels of IL18 were increased, but mRNA expression of Il18 in adipose tissue was significantly decreased in obese mice compared with control mice [106]. Previous studies in Il18−/− mice have indicated that IL18 is involved in glucose metabolism, lipid metabolism, and mitochondrial function [8,9,15]. IL18 deficiency was also shown to inhibit the phosphorylation of STAT3 in the liver, which may play a role in the mechanism of impaired energy metabolism, indicating the possible involvement of the Wnt signaling system [8].

6. Metabolism-Related Genes in Il18−/− Mice

DEGs identified in the microarray analysis of Il18−/− mice that are involved in lipid and glucose metabolism are shown in Table 2.
Atm is required to maintain mitochondrial homeostasis [107]. Regulation of the DNA damage response by Atm involves inflammatory cytokines such as tumor necrosis factor-α and nuclear factor-κB [108]. Atm is implicated in intermediary metabolism through signaling pathways such as insulin and AMPK [109,110]. Aged Atm−/− mice show an increase in blood glucose levels with lower insulin and C-peptide levels, whereas young Atm−/− mice exhibit temporal hyperglycemia during oral glucose challenge comparing to age-matched wild-type controls [111,112]. Atm−/− mice also display disturbances in carbohydrate metabolism, such as glucose intolerance, insulin resistance, and insufficient insulin secretion [111,113]. Furthermore, diet-induced hepatic steatosis is reduced in Atm−/− mice compared with that in wild-type mice [114]. The Atm pathway is associated with oncogenesis [115]. In NASH, Atm mRNA expression accelerates signaling of oncogenic pathways [116,117]. Activation of Atm increases the accumulation of cholesterol [118]. In Il18−/− mice, the expression of Atm is significantly decreased, raising the possibility that IL18 might regulate Atm, resulting in an imbalance of glucose and lipid metabolism.
Casp4 is related to energy metabolism and responds to endoplasmic reticulum (ER) stress [119]. The ER is a crucial site of lipid metabolism, and a number of enzymes related to lipid metabolism exist there [120]. Casp4 has been implicated in inflammasome activation through ER stress [121]. IL18 is an important component of the inflammasome. Decreased expression of Casp4 was observed in Il18−/− mice, which is consistent with these previous studies.
Ccnd1 expression is decreased in Il18−/− mice. We discussed the relationship between IL18, cyclin D1, and lipid metabolism in a previous study [8].
Ifi16 is related to energy metabolism, and both lipid and glucose metabolism are affected by Ifi16 expression [122]. One study showed that increased Ifi16 expression stimulates adipogenesis in mice and humans [123]. Furthermore, the authors found that overexpression of Ifi16 in mice led to obesity. Expression of Ifi16 is significantly decreased in Il18−/− mice, which leads us to speculate that Ifi16 might not be related to obesity in Il18−/− mice.
Nnmt is closely related to energy metabolism, and the expression of Nnmt in liver improves lipid parameters [124]. In humans and mice, the expression of Nnmt is negatively correlated with the levels of lipids, such as total cholesterol, low-density lipoprotein cholesterol, and triglycerides [125]. Another report showed that overexpression of Nnmt in mice led to fatty liver disease and fibrosis [126]. Nnmt expression in adipose tissue was also inversely correlated with insulin sensitivity [127]. In Il18−/− mice, the expression of Nnmt is decreased. The phenotypes of Il18−/− mice are partially consistent with some results of previous these papers.
No studies have examined the relationship between Chrm1 and Hmbs expression and energy metabolism.

7. IL18 and Psychiatric Disorders

Previous studies have revealed that IL18 is closely related to several psychiatric disorders, including depressive disorders and schizophrenia [128]. Serum or plasma levels of IL18 in patients with depression, AD, or mild cognitive impairment were found to be higher than in healthy individuals [129,130]. Although IL18 is abnormally upregulated in neurons and glial cells in AD patients, IL18 levels are not associated with the severity of AD [131,132]. First-episode psychosis patients display increased plasma levels of IL18 that correlate with its severity [133]. An in vitro study using a human neuroblastoma cell line, Sh-sy5y, showed that IL18 promotes amyloid beta (Aβ) production and kinase activity, which is important for tau phosphorylation [134,135]. These findings indicate that IL18 is closely associated with various psychiatric disorders and cognitive impairment. Our study reported that IL18-deficient mice show depressive-like behavioral changes and impairments in learning and memory [10]. In another study, we reported that IL18 might have an adjustive function against stress [136].

8. Psychiatric and Brain Disorder-Related Genes in Il18−/− Mice

DEGs identified in the microarray analysis of Il18−/− mice that are related to psychiatric disorders or psychiatric symptoms are shown in Table 3.
The Atm gene has multiple roles in central neurons. Previous studies have shown that Atm is required for apoptosis of the developing nervous system in response to DNA damage [137,138,139]. Deficiency of Atm in dentate gyrus led to decreased survival of proliferating neurons, suggesting that Atm may have a role in neural progenitor survival or differentiation in the hippocampus [140]. In Il18−/− mice, the expression of Atm is significantly decreased, and neurogenesis in the hippocampus was suppressed in Il18−/− mice compared with that in Il18+/+ mice [10]. Therefore, the histological phenotypes as suppressed neurogenesis in Il18−/− mice may be caused by decreased expression of Atm.
Casp4 is associated with the risk genes for AD [141]. Casp4 expression is increased in the hippocampus and prefrontal cortex of CASP4/APP/PS1 mice, and increased expression of Casp4 leads to hippocampal synaptic plasticity in APP/PS1 mice. Casp4 is also expressed in microglia, and the presence of Casp4 led to more microglia clustered around amyloid plaques [141]. In Il18−/− mice, the expression of Casp4 is significantly decreased. In a previous study, less mature neural cells were observed in dentate gyrus of Il18−/− mice (10); therefore, Casp4 might be one of the genes responsible for the behavioral phenotypes of Il18−/− mice.
Chrm1 is related to various psychiatric disorders, including schizophrenia and mood disorders [142,143]. In patients with schizophrenia, the expression of Chrm1 is decreased in the cortex [144]. Chrm1 encodes a receptor that is highly expressed in glutamatergic neurons [145] and in postsynaptic regions of the hippocampus [146], and is a potential target molecule for schizophrenia treatment [142]. Chrm1 expression is decreased in Il18−/− mice, leading us to speculate that Chrm1 may not be responsible for the behavioral phenotypes of Il18−/− mice.
Npas1 is expressed in neurons in the brain. Npas1 protein is a transcriptional suppressor of neuronal differentiation, development, and maturity functions [147,148]. Furthermore, Npas1-positive neural cells in the ventral pallidum modulate the susceptibility to stressors and anxiety-like behaviors [149]. In our previous study, Il18−/− mice showed a depression-like phenotype, in which Npas1 was upregulated and suppressed neurogenesis in the hippocampus [10]. While Npas1 may be one mediator of the depression-like phenotype in Il18−/− mice [10], further analysis of the brain in these mice, particularly Npas1-positive neural cells, is warranted.
Nnmt is expressed in cholinergic neurons of the hippocampus [150]. In AD patients, Nnmt expression is increased in this area. In a post-mortem study, the expression of Nnmt in the prefrontal cortex was decreased in patients with schizophrenia compared with that in healthy individuals [151]. Patients with bipolar disorders also exhibit decreased serum levels of Nnmt compared with healthy individuals [152]. Nnmt expression is decreased in Il18−/− mice. While Nnmt might be associated with several psychiatric disorders, further analysis of Nnmt in other brain regions, such as the hippocampus or prefrontal cortex, may improve our understanding of these relationships.

9. Conclusions and Future Directions

In this review, we discussed the microarray analysis of DEGs identified in the liver, BAT, and brain of Il18−/− mice. Building on a previous report linking IL18 deficiency to metabolic disorders and depressive-like behavioral changes, we describe here the relationship between IL18 and cancer tumorigenesis, and the potential for IL18 treatment of cancer immunotherapy in combination with immune checkpoint inhibitors. The DEGs commonly expressed in these three tissues may be related to cancer, energy metabolism, and psychiatric disorders. We speculate that the phenotypes of Il18−/− mice may involve aberrations in these genes, and should be investigated in future studies. One limitation of this review is that it was based mainly on our own previous findings. As more research on Il18 mutant mice is reported, thorough comparisons with our previous findings will be required. Although the many roles of IL18 have been revealed through basic and clinical studies (e.g., as a cancer therapy), there have been few clinical trials. Continued translational and clinical research is warranted to further investigate the potential of IL18 as a therapeutic agent.

Author Contributions

K.Y. and H.M. designed this review, contributed the psychiatric disorder section and wrote the manuscript. M.H. and H.O. contributed the cancer section. N.G. and C.Y. contributed the energy metabolism section. Y.W. performed molecular analysis. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by JSPS KAKENHI (Grant Numbers 20K16680 and 23K06999) and a Hyogo Medical University Grant for Research Promotion, 2022.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The datasets shown and/or analyzed in the present study are available from the corresponding author upon reasonable request.

Acknowledgments

We thank Nobutaka Okamura and Mina Nishimura for their technical support, Nobutaka Okamura for his assistance with animal care and the collection of samples, and Mina Nishimura for clerical assistance. We thank the funders listed above for supporting our study.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Okamura, H.; Tsutsi, H.; Komatsu, T.; Yutsudo, M.; Hakura, A.; Tanimoto, T.; Torigoe, K.; Okura, T.; Nukada, Y.; Hattori, K.; et al. Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature 1995, 378, 88–91. [Google Scholar] [CrossRef] [PubMed]
  2. Ghayur, T.; Banerjee, S.; Hugunin, M.; Butler, D.; Herzog, L.; Carter, A.; Quintal, L.; Sekut, L.; Talanian, R.; Paskind, M.; et al. Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production. Nature 1997, 386, 619–623. [Google Scholar] [CrossRef] [PubMed]
  3. Okamura, H.; Tsutsui, H.; Kashiwamura, S.; Yoshimoto, T.; Nakanishi, K. Interleukin-18: A novel cytokine that augments both innate and acquired immunity. Adv. Immunol. 1998, 70, 281–312. [Google Scholar] [CrossRef] [PubMed]
  4. Sugawara, S.; Uehara, A.; Nochi, T.; Yamaguchi, T.; Ueda, H.; Sugiyama, A.; Hanzawa, K.; Kumagai, K.; Okamura, H.; Takada, H. Neutrophil proteinase 3-mediated induction of bioactive IL-18 secretion by human oral epithelial cells. J. Immunol. 2001, 167, 6568–6575. [Google Scholar] [CrossRef] [PubMed]
  5. Tsutsui, H.; Kayagaki, N.; Kuida, K.; Nakano, H.; Hayashi, N.; Takeda, K.; Matsui, K.; Kashiwamura, S.; Hada, T.; Akira, S.; et al. Caspase-1-independent, Fas/Fas ligand-mediated IL-18 secretion from macrophages causes acute liver injury in mice. Immunity 1999, 11, 359–367. [Google Scholar] [CrossRef] [PubMed]
  6. Yamanishi, K.; Miyauchi, M.; Mukai, K.; Hashimoto, T.; Uwa, N.; Seino, H.; Li, W.; Gamachi, N.; Hata, M.; Kuwahara-Otani, S.; et al. Exploring Molecular Mechanisms Involved in the Development of the Depression-Like Phenotype in Interleukin-18-Deficient Mice. BioMed Res. Int. 2021, 2021, 9975865. [Google Scholar] [CrossRef]
  7. Prinz, M.; Hanisch, U.K. Murine microglial cells produce and respond to interleukin-18. J. Neurochem. 1999, 72, 2215–2218. [Google Scholar] [CrossRef]
  8. Yamanishi, K.; Maeda, S.; Kuwahara-Otani, S.; Watanabe, Y.; Yoshida, M.; Ikubo, K.; Okuzaki, D.; El-Darawish, Y.; Li, W.; Nakasho, K.; et al. Interleukin-18-deficient mice develop dyslipidemia resulting in nonalcoholic fatty liver disease and steatohepatitis. Transl. Res. J. Lab. Clin. Med. 2016, 173, 101–114.e17. [Google Scholar] [CrossRef]
  9. Yamanishi, K.; Maeda, S.; Kuwahara-Otani, S.; Hashimoto, T.; Ikubo, K.; Mukai, K.; Nakasho, K.; Gamachi, N.; El-Darawish, Y.; Li, W.; et al. Deficiency in interleukin-18 promotes differentiation of brown adipose tissue resulting in fat accumulation despite dyslipidemia. J. Transl. Med. 2018, 16, 314. [Google Scholar] [CrossRef]
  10. Yamanishi, K.; Doe, N.; Mukai, K.; Ikubo, K.; Hashimoto, T.; Uwa, N.; Sumida, M.; El-Darawish, Y.; Gamachi, N.; Li, W.; et al. Interleukin-18-deficient mice develop hippocampal abnormalities related to possible depressive-like behaviors. Neuroscience 2019, 408, 147–160. [Google Scholar] [CrossRef]
  11. Kokai, M.; Kashiwamura, S.; Okamura, H.; Ohara, K.; Morita, Y. Plasma interleukin-18 levels in patients with psychiatric disorders. J. Immunother. 2002, 25 (Suppl. S1), S68–S71. [Google Scholar] [CrossRef] [PubMed]
  12. Ma, Z.; Li, W.; Yoshiya, S.; Xu, Y.; Hata, M.; El-Darawish, Y.; Markova, T.; Yamanishi, K.; Yamanishi, H.; Tahara, H.; et al. Augmentation of Immune Checkpoint Cancer Immunotherapy with IL18. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2016, 22, 2969–2980. [Google Scholar] [CrossRef] [PubMed]
  13. El-Darawish, Y.; Li, W.; Yamanishi, K.; Pencheva, M.; Oka, N.; Yamanishi, H.; Matsuyama, T.; Tanaka, Y.; Minato, N.; Okamura, H. Frontline Science: IL-18 primes murine NK cells for proliferation by promoting protein synthesis, survival, and autophagy. J. Leukoc. Biol. 2018, 104, 253–264. [Google Scholar] [CrossRef] [PubMed]
  14. Oka, N.; Markova, T.; Tsuzuki, K.; Li, W.; El-Darawish, Y.; Pencheva-Demireva, M.; Yamanishi, K.; Yamanishi, H.; Sakagami, M.; Tanaka, Y.; et al. IL-12 regulates the expansion, phenotype, and function of murine NK cells activated by IL-15 and IL-18. Cancer Immunol. Immunother. CII 2020, 69, 1699–1712. [Google Scholar] [CrossRef] [PubMed]
  15. Netea, M.G.; Joosten, L.A.; Lewis, E.; Jensen, D.R.; Voshol, P.J.; Kullberg, B.J.; Tack, C.J.; van Krieken, H.; Kim, S.H.; Stalenhoef, A.F.; et al. Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance. Nat. Med. 2006, 12, 650–656. [Google Scholar] [CrossRef]
  16. Lisboa, S.F.; Issy, A.C.; Biojone, C.; Montezuma, K.; Fattori, V.; Del-Bel, E.A.; Guimarães, F.S.; Cunha, F.Q.; Verri, W.A.; Joca, S.R.L. Mice lacking interleukin-18 gene display behavioral changes in animal models of psychiatric disorders: Possible involvement of immunological mechanisms. J. Neuroimmunol. 2018, 314, 58–66. [Google Scholar] [CrossRef]
  17. Yamanishi, K.; Hashimoto, T.; Miyauchi, M.; Mukai, K.; Ikubo, K.; Uwa, N.; Watanabe, Y.; Ikawa, T.; Okuzaki, D.; Okamura, H.; et al. Analysis of genes linked to depressive-like behaviors in interleukin-18-deficient mice: Gene expression profiles in the brain. Biomed. Rep. 2020, 12, 3–10. [Google Scholar] [CrossRef]
  18. Yamanishi, K.; Doe, N.; Sumida, M.; Watanabe, Y.; Yoshida, M.; Yamamoto, H.; Xu, Y.; Li, W.; Yamanishi, H.; Okamura, H.; et al. Hepatocyte nuclear factor 4 alpha is a key factor related to depression and physiological homeostasis in the mouse brain. PLoS ONE 2015, 10, e0119021. [Google Scholar] [CrossRef]
  19. Ikubo, K.; Yamanishi, K.; Doe, N.; Hashimoto, T.; Sumida, M.; Watanabe, Y.; El-Darawish, Y.; Li, W.; Okamura, H.; Yamanishi, H.; et al. Molecular analysis of the mouse brain exposed to chronic mild stress: The influence of hepatocyte nuclear factor 4α on physiological homeostasis. Mol. Med. Rep. 2017, 16, 301–309. [Google Scholar] [CrossRef]
  20. Ahmed, A.; Klotz, R.; Köhler, S.; Giese, N.; Hackert, T.; Springfeld, C.; Jäger, D.; Halama, N. Immune features of the peritumoral stroma in pancreatic ductal adenocarcinoma. Front. Immunol. 2022, 13, 947407. [Google Scholar] [CrossRef]
  21. Bellone, G.; Smirne, C.; Mauri, F.A.; Tonel, E.; Carbone, A.; Buffolino, A.; Dughera, L.; Robecchi, A.; Pirisi, M.; Emanuelli, G. Cytokine expression profile in human pancreatic carcinoma cells and in surgical specimens: Implications for survival. Cancer Immunol. Immunother. CII 2006, 55, 684–698. [Google Scholar] [CrossRef] [PubMed]
  22. Sun, Q.; Fan, G.; Zhuo, Q.; Dai, W.; Ye, Z.; Ji, S.; Xu, W.; Liu, W.; Hu, Q.; Zhang, Z.; et al. Pin1 promotes pancreatic cancer progression and metastasis by activation of NF-κB-IL-18 feedback loop. Cell Prolif. 2020, 53, e12816. [Google Scholar] [CrossRef] [PubMed]
  23. Usul Afsar, Ç.; Karabulut, M.; Karabulut, S.; Alis, H.; Gonenc, M.; Dagoglu, N.; Serilmez, M.; Tas, F. Circulating interleukin-18 (IL-18) is a predictor of response to gemcitabine based chemotherapy in patients with pancreatic adenocarcinoma. J. Infect. Chemother. Off. J. Jpn. Soc. Chemother. 2017, 23, 196–200. [Google Scholar] [CrossRef] [PubMed]
  24. Carbone, A.; Vizio, B.; Novarino, A.; Mauri, F.A.; Geuna, M.; Robino, C.; Brondino, G.; Prati, A.; Giacobino, A.; Campra, D.; et al. IL-18 paradox in pancreatic carcinoma: Elevated serum levels of free IL-18 are correlated with poor survival. J. Immunother. 2009, 32, 920–931. [Google Scholar] [CrossRef] [PubMed]
  25. Ding, L.; Zhao, X.; Zhu, N.; Zhao, M.; Hu, Q.; Ni, Y. The balance of serum IL-18/IL-37 levels is disrupted during the development of oral squamous cell carcinoma. Surg. Oncol. 2020, 32, 99–107. [Google Scholar] [CrossRef] [PubMed]
  26. Robertson, M.J.; Kirkwood, J.M.; Logan, T.F.; Koch, K.M.; Kathman, S.; Kirby, L.C.; Bell, W.N.; Thurmond, L.M.; Weisenbach, J.; Dar, M.M. A dose-escalation study of recombinant human interleukin-18 using two different schedules of administration in patients with cancer. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2008, 14, 3462–3469. [Google Scholar] [CrossRef]
  27. Tarhini, A.A.; Millward, M.; Mainwaring, P.; Kefford, R.; Logan, T.; Pavlick, A.; Kathman, S.J.; Laubscher, K.H.; Dar, M.M.; Kirkwood, J.M. A phase 2, randomized study of SB-485232, rhIL-18, in patients with previously untreated metastatic melanoma. Cancer 2009, 115, 859–868. [Google Scholar] [CrossRef]
  28. Robertson, M.J.; Mier, J.W.; Logan, T.; Atkins, M.; Koon, H.; Koch, K.M.; Kathman, S.; Pandite, L.N.; Oei, C.; Kirby, L.C.; et al. Clinical and biological effects of recombinant human interleukin-18 administered by intravenous infusion to patients with advanced cancer. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2006, 12 Pt 1, 4265–4273. [Google Scholar] [CrossRef]
  29. Zhou, T.; Damsky, W.; Weizman, O.E.; McGeary, M.K.; Hartmann, K.P.; Rosen, C.E.; Fischer, S.; Jackson, R.; Flavell, R.A.; Wang, J.; et al. IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy. Nature 2020, 583, 609–614. [Google Scholar] [CrossRef]
  30. Liu, W.; Han, B.; Sun, B.; Gao, Y.; Huang, Y.; Hu, M. Overexpression of interleukin-18 induces growth inhibition, apoptosis and gene expression changes in a human tongue squamous cell carcinoma cell line. J. Int. Med. Res. 2012, 40, 537–544. [Google Scholar] [CrossRef]
  31. Zhang, J.; Pan, C.; Xu, T.; Niu, Z.; Ma, C.; Xu, C. Interleukin 18 augments growth ability via NF-κB and p38/ATF2 pathways by targeting cyclin B1, cyclin B2, cyclin A2, and Bcl-2 in BRL-3A rat liver cells. Gene 2015, 563, 45–51. [Google Scholar] [CrossRef] [PubMed]
  32. Jung, M.K.; Park, Y.; Song, S.B.; Cheon, S.Y.; Park, S.; Houh, Y.; Ha, S.; Kim, H.J.; Park, J.M.; Kim, T.S.; et al. Erythroid differentiation regulator 1, an interleukin 18-regulated gene, acts as a metastasis suppressor in melanoma. J. Investig. Dermatol. 2011, 131, 2096–2104. [Google Scholar] [CrossRef] [PubMed]
  33. Houh, Y.K.; Kim, K.E.; Park, H.J.; Cho, D. Roles of Erythroid Differentiation Regulator 1 (Erdr1) on Inflammatory Skin Diseases. Int. J. Mol. Sci. 2016, 17, 2059. [Google Scholar] [CrossRef] [PubMed]
  34. Jung, M.K.; Houh, Y.K.; Ha, S.; Yang, Y.; Kim, D.; Kim, T.S.; Yoon, S.R.; Bang, S.I.; Cho, B.J.; Lee, W.J.; et al. Recombinant Erdr1 suppresses the migration and invasion ability of human gastric cancer cells, SNU-216, through the JNK pathway. Immunol. Lett. 2013, 150, 145–151. [Google Scholar] [CrossRef] [PubMed]
  35. Lee, J.; Jung, M.K.; Park, H.J.; Kim, K.E.; Cho, D. Erdr1 Suppresses Murine Melanoma Growth via Regulation of Apoptosis. Int. J. Mol. Sci. 2016, 17, 107. [Google Scholar] [CrossRef]
  36. Helmbach, H.; Rossmann, E.; Kern, M.A.; Schadendorf, D. Drug-resistance in human melanoma. Int. J. Cancer 2001, 93, 617–622. [Google Scholar] [CrossRef] [PubMed]
  37. Fofaria, N.M.; Srivastava, S.K. Critical role of STAT3 in melanoma metastasis through anoikis resistance. Oncotarget 2014, 5, 7051–7064. [Google Scholar] [CrossRef] [PubMed]
  38. Yu, H.; Pardoll, D.; Jove, R. STATs in cancer inflammation and immunity: A leading role for STAT3. Nat. Rev. Cancer 2009, 9, 798–809. [Google Scholar] [CrossRef]
  39. Lee, H.R.; Huh, S.Y.; Hur, D.Y.; Jeong, H.; Kim, T.S.; Kim, S.Y.; Park, S.B.; Yang, Y.; Bang, S.I.; Park, H.; et al. ERDR1 enhances human NK cell cytotoxicity through an actin-regulated degranulation-dependent pathway. Cell. Immunol. 2014, 292, 78–84. [Google Scholar] [CrossRef]
  40. Liu, Y.R.; Hu, Y.; Zeng, Y.; Li, Z.X.; Zhang, H.B.; Deng, J.L.; Wang, G. Neurexophilin and PC-esterase domain family member 4 (NXPE4) and prostate androgen-regulated mucin-like protein 1 (PARM1) as prognostic biomarkers for colorectal cancer. J. Cell. Biochem. 2019, 120, 18041–18052. [Google Scholar] [CrossRef]
  41. Yassin, M.; Kissow, H.; Vainer, B.; Joseph, P.D.; Hay-Schmidt, A.; Olsen, J.; Pedersen, A.E. Cytoglobin affects tumorigenesis and the expression of ulcerative colitis-associated genes under chemically induced colitis in mice. Sci. Rep. 2018, 8, 6905. [Google Scholar] [CrossRef]
  42. Yang, C.; Wang, T.; Zhu, S.; Zong, Z.; Luo, C.; Zhao, Y.; Liu, J.; Li, T.; Liu, X.; Liu, C.; et al. Nicotinamide N-Methyltransferase Remodeled Cell Metabolism and Aggravated Proinflammatory Responses by Activating STAT3/IL1β/PGE(2) Pathway. ACS Omega 2022, 7, 37509–37519. [Google Scholar] [CrossRef] [PubMed]
  43. You, Z.; Liu, Y.; Liu, X. Nicotinamide N-methyltransferase enhances the progression of prostate cancer by stabilizing sirtuin 1. Oncol. Lett. 2018, 15, 9195–9201. [Google Scholar] [CrossRef] [PubMed]
  44. Hrašovec, S.; Hauptman, N.; Glavač, D.; Jelenc, F.; Ravnik-Glavač, M. TMEM25 is a candidate biomarker methylated and down-regulated in colorectal cancer. Dis. Markers 2013, 34, 93–104. [Google Scholar] [CrossRef]
  45. Doolan, P.; Clynes, M.; Kennedy, S.; Mehta, J.P.; Germano, S.; Ehrhardt, C.; Crown, J.; O’Driscoll, L. TMEM25, REPS2 and Meis 1: Favourable prognostic and predictive biomarkers for breast cancer. Tumour Biol. J. Int. Soc. Oncodevelopmental Biol. Med. 2009, 30, 200–209. [Google Scholar] [CrossRef] [PubMed]
  46. Katoh, M.; Katoh, M. Identification and characterization of human TMEM25 and mouse Tmem25 genes in silico. Oncol. Rep. 2004, 12, 429–433. [Google Scholar] [CrossRef] [PubMed]
  47. Chakravarti, D.; Hu, B.; Mao, X.; Rashid, A.; Li, J.; Li, J.; Liao, W.T.; Whitley, E.M.; Dey, P.; Hou, P.; et al. Telomere dysfunction activates YAP1 to drive tissue inflammation. Nat. Commun. 2020, 11, 4766. [Google Scholar] [CrossRef]
  48. Angèle, S.; Hall, J. The ATM gene and breast cancer: Is it really a risk factor? Mutat. Res. 2000, 462, 167–178. [Google Scholar] [CrossRef]
  49. Renwick, A.; Thompson, D.; Seal, S.; Kelly, P.; Chagtai, T.; Ahmed, M.; North, B.; Jayatilake, H.; Barfoot, R.; Spanova, K.; et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat. Genet. 2006, 38, 873–875. [Google Scholar] [CrossRef]
  50. Hsu, F.C.; Roberts, N.J.; Childs, E.; Porter, N.; Rabe, K.G.; Borgida, A.; Ukaegbu, C.; Goggins, M.G.; Hruban, R.H.; Zogopoulos, G.; et al. Risk of Pancreatic Cancer Among Individuals With Pathogenic Variants in the ATM Gene. JAMA Oncol. 2021, 7, 1664–1668. [Google Scholar] [CrossRef]
  51. Martino, C.; Pandya, D.; Lee, R.; Levy, G.; Lo, T.; Lobo, S.; Frank, R.C. ATM-Mutated Pancreatic Cancer: Clinical and Molecular Response to Gemcitabine/Nab-Paclitaxel After Genome-Based Therapy Resistance. Pancreas 2020, 49, 143–147. [Google Scholar] [CrossRef] [PubMed]
  52. Kim, C.W.; Cha, J.M.; Kwak, M.S. Identification of Potential Biomarkers and Biological Pathways for Poor Clinical Outcome in Mucinous Colorectal Adenocarcinoma. Cancers 2021, 13, 3280. [Google Scholar] [CrossRef] [PubMed]
  53. Hsu, C.H.; Hsu, C.W.; Hsueh, C.; Wang, C.L.; Wu, Y.C.; Wu, C.C.; Liu, C.C.; Yu, J.S.; Chang, Y.S.; Yu, C.J. Identification and Characterization of Potential Biomarkers by Quantitative Tissue Proteomics of Primary Lung Adenocarcinoma. Mol. Cell. Proteom. MCP 2016, 15, 2396–2410. [Google Scholar] [CrossRef] [PubMed]
  54. Sadhra, S.; Kurmi, O.P.; Sadhra, S.S.; Lam, K.B.; Ayres, J.G. Occupational COPD and job exposure matrices: A systematic review and meta-analysis. Int. J. Chronic Obstr. Pulm. Dis. 2017, 12, 725–734. [Google Scholar] [CrossRef] [PubMed]
  55. Reddy, R.B.; Khora, S.S.; Suresh, A. Molecular prognosticators in clinically and pathologically distinct cohorts of head and neck squamous cell carcinoma-A meta-analysis approach. PLoS ONE 2019, 14, e0218989. [Google Scholar] [CrossRef]
  56. Li, S.; Wang, C.; Liu, X.; Hua, S.; Liu, X. The roles of AXIN2 in tumorigenesis and epigenetic regulation. Fam. Cancer 2015, 14, 325–331. [Google Scholar] [CrossRef] [PubMed]
  57. Kim, J.S.; Park, S.Y.; Lee, S.A.; Park, M.G.; Yu, S.K.; Lee, M.H.; Park, M.R.; Kim, S.G.; Oh, J.S.; Lee, S.Y.; et al. MicroRNA-205 suppresses the oral carcinoma oncogenic activity via down-regulation of Axin-2 in KB human oral cancer cell. Mol. Cell. Biochem. 2014, 387, 71–79. [Google Scholar] [CrossRef] [PubMed]
  58. Ying, Y.; Tao, Q. Epigenetic disruption of the WNT/beta-catenin signaling pathway in human cancers. Epigenetics 2009, 4, 307–312. [Google Scholar] [CrossRef]
  59. Lustig, B.; Jerchow, B.; Sachs, M.; Weiler, S.; Pietsch, T.; Karsten, U.; van de Wetering, M.; Clevers, H.; Schlag, P.M.; Birchmeier, W.; et al. Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors. Mol. Cell. Biol. 2002, 22, 1184–1193. [Google Scholar] [CrossRef]
  60. Kim, W.K.; Byun, W.S.; Chung, H.J.; Oh, J.; Park, H.J.; Choi, J.S.; Lee, S.K. Esculetin suppresses tumor growth and metastasis by targeting Axin2/E-cadherin axis in colorectal cancer. Biochem. Pharmacol. 2018, 152, 71–83. [Google Scholar] [CrossRef]
  61. Schulten, H.J.; Hussein, D.; Al-Adwani, F.; Karim, S.; Al-Maghrabi, J.; Al-Sharif, M.; Jamal, A.; Bakhashab, S.; Weaver, J.; Al-Ghamdi, F.; et al. Microarray expression profiling identifies genes, including cytokines, and biofunctions, as diapedesis, associated with a brain metastasis from a papillary thyroid carcinoma. Am. J. Cancer Res. 2016, 6, 2140–2161. [Google Scholar] [PubMed]
  62. Terlizzi, M.; Colarusso, C.; De Rosa, I.; De Rosa, N.; Somma, P.; Curcio, C.; Sanduzzi, A.; Micheli, P.; Molino, A.; Saccomanno, A.; et al. Circulating and tumor-associated caspase-4: A novel diagnostic and prognostic biomarker for non-small cell lung cancer. Oncotarget 2018, 9, 19356–19367. [Google Scholar] [CrossRef] [PubMed]
  63. Wang, Z.; Ni, F.; Yu, F.; Cui, Z.; Zhu, X.; Chen, J. Prognostic significance of mRNA expression of CASPs in gastric cancer. Oncol. Lett. 2019, 18, 4535–4554. [Google Scholar] [CrossRef] [PubMed]
  64. Shibamoto, M.; Hirata, H.; Eguchi, H.; Sawada, G.; Sakai, N.; Kajiyama, Y.; Mimori, K. The loss of CASP4 expression is associated with poor prognosis in esophageal squamous cell carcinoma. Oncol. Lett. 2017, 13, 1761–1766. [Google Scholar] [CrossRef]
  65. Zahalka, A.H.; Arnal-Estapé, A.; Maryanovich, M.; Nakahara, F.; Cruz, C.D.; Finley, L.W.S.; Frenette, P.S. Adrenergic nerves activate an angio-metabolic switch in prostate cancer. Science 2017, 358, 321–326. [Google Scholar] [CrossRef]
  66. Yin, Q.Q.; Xu, L.H.; Zhang, M.; Xu, C. Muscarinic acetylcholine receptor M1 mediates prostate cancer cell migration and invasion through hedgehog signaling. Asian J. Androl. 2018, 20, 608–614. [Google Scholar] [CrossRef]
  67. Zhang, L.; Wu, L.L.; Huan, H.B.; Wen, X.D.; Yang, D.P.; Chen, D.F.; Xia, F. Activation of muscarinic acetylcholine receptor 1 promotes invasion of hepatocellular carcinoma by inducing epithelial-mesenchymal transition. Anti-Cancer Drugs 2020, 31, 908–917. [Google Scholar] [CrossRef]
  68. Renz, B.W.; Tanaka, T.; Sunagawa, M.; Takahashi, R.; Jiang, Z.; Macchini, M.; Dantes, Z.; Valenti, G.; White, R.A.; Middelhoff, M.A.; et al. Cholinergic Signaling via Muscarinic Receptors Directly and Indirectly Suppresses Pancreatic Tumorigenesis and Cancer Stemness. Cancer Discov. 2018, 8, 1458–1473. [Google Scholar] [CrossRef]
  69. Tang, H.; Guo, Q.; Zhang, C.; Zhu, J.; Yang, H.; Zou, Y.L.; Yan, Y.; Hong, D.; Sou, T.; Yan, X.M. Identification of an intermediate signature that marks the initial phases of the colorectal adenoma-carcinoma transition. Int. J. Mol. Med. 2010, 26, 631–641. [Google Scholar] [CrossRef]
  70. Yang, C.A.; Huang, H.Y.; Chang, Y.S.; Lin, C.L.; Lai, I.L.; Chang, J.G. DNA-Sensing and Nuclease Gene Expressions as Markers for Colorectal Cancer Progression. Oncology 2017, 92, 115–124. [Google Scholar] [CrossRef]
  71. Cai, H.; Yan, L.; Liu, N.; Xu, M.; Cai, H. IFI16 promotes cervical cancer progression by upregulating PD-L1 in immunomicroenvironment through STING-TBK1-NF-kB pathway. Biomed. Pharmacother. = Biomed. Pharmacother. 2020, 123, 109790. [Google Scholar] [CrossRef] [PubMed]
  72. Unterholzner, L.; Keating, S.E.; Baran, M.; Horan, K.A.; Jensen, S.B.; Sharma, S.; Sirois, C.M.; Jin, T.; Latz, E.; Xiao, T.S.; et al. IFI16 is an innate immune sensor for intracellular DNA. Nat. Immunol. 2010, 11, 997–1004. [Google Scholar] [CrossRef] [PubMed]
  73. Kerur, N.; Veettil, M.V.; Sharma-Walia, N.; Bottero, V.; Sadagopan, S.; Otageri, P.; Chandran, B. IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi Sarcoma-associated herpesvirus infection. Cell Host Microbe 2011, 9, 363–375. [Google Scholar] [CrossRef]
  74. Lin, W.; Zhao, Z.; Ni, Z.; Zhao, Y.; Du, W.; Chen, S. IFI16 restoration in hepatocellular carcinoma induces tumour inhibition via activation of p53 signals and inflammasome. Cell Prolif. 2017, 50, e12392. [Google Scholar] [CrossRef]
  75. Song, A.; Chen, Y.F.; Thamatrakoln, K.; Storm, T.A.; Krensky, A.M. RFLAT-1: A new zinc finger transcription factor that activates RANTES gene expression in T lymphocytes. Immunity 1999, 10, 93–103. [Google Scholar] [CrossRef] [PubMed]
  76. Tetreault, M.P.; Yang, Y.; Katz, J.P. Krüppel-like factors in cancer. Nat. Rev. Cancer 2013, 13, 701–713. [Google Scholar] [CrossRef]
  77. Fernandez-Zapico, M.E.; Lomberk, G.A.; Tsuji, S.; DeMars, C.J.; Bardsley, M.R.; Lin, Y.H.; Almada, L.L.; Han, J.J.; Mukhopadhyay, D.; Ordog, T.; et al. A functional family-wide screening of SP/KLF proteins identifies a subset of suppressors of KRAS-mediated cell growth. Biochem. J. 2011, 435, 529–537. [Google Scholar] [CrossRef]
  78. Wang, Q.; Peng, R.; Wang, B.; Wang, J.; Yu, W.; Liu, Y.; Shi, G. Transcription factor KLF13 inhibits AKT activation and suppresses the growth of prostate carcinoma cells. Cancer Biomark. Sect. A Dis. Markers 2018, 22, 533–541. [Google Scholar] [CrossRef]
  79. Yao, W.; Jiao, Y.; Zhou, Y.; Luo, X. KLF13 suppresses the proliferation and growth of colorectal cancer cells through transcriptionally inhibiting HMGCS1-mediated cholesterol biosynthesis. Cell Biosci. 2020, 10, 76. [Google Scholar] [CrossRef]
  80. Nemer, M.; Horb, M.E. The KLF family of transcriptional regulators in cardiomyocyte proliferation and differentiation. Cell Cycle 2007, 6, 117–121. [Google Scholar] [CrossRef]
  81. Henson, B.J.; Gollin, S.M. Overexpression of KLF13 and FGFR3 in oral cancer cells. Cytogenet. Genome Res. 2010, 128, 192–198. [Google Scholar] [CrossRef] [PubMed]
  82. Wang, L.; Zhong, Y.; Yang, B.; Zhu, Y.; Zhu, X.; Xia, Z.; Xu, J.; Xu, L. LINC00958 facilitates cervical cancer cell proliferation and metastasis by sponging miR-625-5p to upregulate LRRC8E expression. J. Cell. Biochem. 2020, 121, 2500–2509. [Google Scholar] [CrossRef] [PubMed]
  83. Zhu, Q.; Wang, S.; Shi, Y. LncRNA PCAT6 activated by SP1 facilitates the progression of breast cancer by the miR-326/LRRC8E axis. Anti-Cancer Drugs 2022, 33, 178–190. [Google Scholar] [CrossRef]
  84. Sullivan, J.P.; Minna, J.D. Tumor oncogenotypes and lung cancer stem cell identity. Cell Stem Cell 2010, 7, 2–4. [Google Scholar] [CrossRef] [PubMed]
  85. Ceder, J.A.; Aalders, T.W.; Schalken, J.A. Label retention and stem cell marker expression in the developing and adult prostate identifies basal and luminal epithelial stem cell subpopulations. Stem Cell Res. Ther. 2017, 8, 95. [Google Scholar] [CrossRef]
  86. Dall, G.V.; Vieusseux, J.L.; Korach, K.S.; Arao, Y.; Hewitt, S.C.; Hamilton, K.J.; Dzierzak, E.; Boon, W.C.; Simpson, E.R.; Ramsay, R.G.; et al. SCA-1 Labels a Subset of Estrogen-Responsive Bipotential Repopulating Cells within the CD24(+) CD49f(hi) Mammary Stem Cell-Enriched Compartment. Stem Cell Rep. 2017, 8, 417–431. [Google Scholar] [CrossRef]
  87. Batts, T.D.; Machado, H.L.; Zhang, Y.; Creighton, C.J.; Li, Y.; Rosen, J.M. Stem cell antigen-1 (sca-1) regulates mammary tumor development and cell migration. PLoS ONE 2011, 6, e27841. [Google Scholar] [CrossRef]
  88. Li, S.; Zhuang, Z.; Wu, T.; Lin, J.C.; Liu, Z.X.; Zhou, L.F.; Dai, T.; Lu, L.; Ju, H.Q. Nicotinamide nucleotide transhydrogenase-mediated redox homeostasis promotes tumor growth and metastasis in gastric cancer. Redox Biol. 2018, 18, 246–255. [Google Scholar] [CrossRef]
  89. Chortis, V.; Taylor, A.E.; Doig, C.L.; Walsh, M.D.; Meimaridou, E.; Jenkinson, C.; Rodriguez-Blanco, G.; Ronchi, C.L.; Jafri, A.; Metherell, L.A.; et al. Nicotinamide Nucleotide Transhydrogenase as a Novel Treatment Target in Adrenocortical Carcinoma. Endocrinology 2018, 159, 2836–2849. [Google Scholar] [CrossRef]
  90. Ward, N.P.; Kang, Y.P.; Falzone, A.; Boyle, T.A.; DeNicola, G.M. Nicotinamide nucleotide transhydrogenase regulates mitochondrial metabolism in NSCLC through maintenance of Fe-S protein function. J. Exp. Med. 2020, 217, e20191689. [Google Scholar] [CrossRef]
  91. Claudio, J.O.; Zhu, Y.X.; Benn, S.J.; Shukla, A.H.; McGlade, C.J.; Falcioni, N.; Stewart, A.K. HACS1 encodes a novel SH3-SAM adaptor protein differentially expressed in normal and malignant hematopoietic cells. Oncogene 2001, 20, 5373–5377. [Google Scholar] [CrossRef] [PubMed]
  92. Yamada, H.; Yanagisawa, K.; Tokumaru, S.; Taguchi, A.; Nimura, Y.; Osada, H.; Nagino, M.; Takahashi, T. Detailed characterization of a homozygously deleted region corresponding to a candidate tumor suppressor locus at 21q11-21 in human lung cancer. Genes Chromosomes Cancer 2008, 47, 810–818. [Google Scholar] [CrossRef] [PubMed]
  93. Noll, J.E.; Hewett, D.R.; Williams, S.A.; Vandyke, K.; Kok, C.; To, L.B.; Zannettino, A.C. SAMSN1 is a tumor suppressor gene in multiple myeloma. Neoplasia 2014, 16, 572–585. [Google Scholar] [CrossRef]
  94. Kanda, M.; Shimizu, D.; Sueoka, S.; Nomoto, S.; Oya, H.; Takami, H.; Ezaka, K.; Hashimoto, R.; Tanaka, Y.; Kobayashi, D.; et al. Prognostic relevance of SAMSN1 expression in gastric cancer. Oncol. Lett. 2016, 12, 4708–4716. [Google Scholar] [CrossRef] [PubMed]
  95. Yan, Y.; Zhang, L.; Xu, T.; Zhou, J.; Qin, R.; Chen, C.; Zou, Y.; Fu, D.; Hu, G.; Chen, J.; et al. SAMSN1 is highly expressed and associated with a poor survival in glioblastoma multiforme. PLoS ONE 2013, 8, e81905. [Google Scholar] [CrossRef] [PubMed]
  96. Sueoka, S.; Kanda, M.; Sugimoto, H.; Shimizu, D.; Nomoto, S.; Oya, H.; Takami, H.; Ezaka, K.; Hashimoto, R.; Tanaka, Y.; et al. Suppression of SAMSN1 Expression is Associated with the Malignant Phenotype of Hepatocellular Carcinoma. Ann. Surg. Oncol. 2015, 22 (Suppl. S3), S1453–S1460. [Google Scholar] [CrossRef]
  97. Zhuang, H.; Han, J.; Cheng, L.; Liu, S.L. A Positive Causal Influence of IL-18 Levels on the Risk of T2DM: A Mendelian Randomization Study. Front. Genet. 2019, 10, 295. [Google Scholar] [CrossRef] [PubMed]
  98. Moriwaki, Y.; Yamamoto, T.; Shibutani, Y.; Aoki, E.; Tsutsumi, Z.; Takahashi, S.; Okamura, H.; Koga, M.; Fukuchi, M.; Hada, T. Elevated levels of interleukin-18 and tumor necrosis factor-alpha in serum of patients with type 2 diabetes mellitus: Relationship with diabetic nephropathy. Metab. Clin. Exp. 2003, 52, 605–608. [Google Scholar] [CrossRef]
  99. Zaharieva, E.; Kamenov, Z.; Velikova, T.; Tsakova, A.; El-Darawish, Y.; Okamura, H. Interleukin-18 serum level is elevated in type 2 diabetes and latent autoimmune diabetes. Endocr. Connect. 2018, 7, 179–185. [Google Scholar] [CrossRef]
  100. Fischer, C.P.; Perstrup, L.B.; Berntsen, A.; Eskildsen, P.; Pedersen, B.K. Elevated plasma interleukin-18 is a marker of insulin-resistance in type 2 diabetic and non-diabetic humans. Clin. Immunol. 2005, 117, 152–160. [Google Scholar] [CrossRef]
  101. Nedeva, I.; Gateva, A.; Assyov, Y.; Karamfilova, V.; Hristova, J.; Yamanishi, K.; Kamenov, Z.; Okamura, H. IL-18 Serum Levels in Patients with Obesity, Prediabetes and Newly Diagnosed Type 2 Diabetes. Iran. J. Immunol. IJI 2022, 19, 193–200. [Google Scholar] [CrossRef] [PubMed]
  102. Kabakchieva, P.; Gateva, A.; Velikova, T.; Georgiev, T.; Yamanishi, K.; Okamura, H.; Kamenov, Z. Elevated levels of interleukin-18 are associated with several indices of general and visceral adiposity and insulin resistance in women with polycystic ovary syndrome. Arch. Endocrinol. Metab. 2022, 66, 3–11. [Google Scholar] [CrossRef] [PubMed]
  103. Hung, J.; McQuillan, B.M.; Chapman, C.M.; Thompson, P.L.; Beilby, J.P. Elevated interleukin-18 levels are associated with the metabolic syndrome independent of obesity and insulin resistance. Arterioscler. Thromb. Vasc. Biol. 2005, 25, 1268–1273. [Google Scholar] [CrossRef] [PubMed]
  104. Olusi, S.O.; Al-Awadhi, A.; Abraham, M. Relations of serum interleukin 18 levels to serum lipid and glucose concentrations in an apparently healthy adult population. Horm. Res. 2003, 60, 29–33. [Google Scholar] [CrossRef] [PubMed]
  105. Esposito, K.; Pontillo, A.; Ciotola, M.; Di Palo, C.; Grella, E.; Nicoletti, G.; Giugliano, D. Weight loss reduces interleukin-18 levels in obese women. J. Clin. Endocrinol. Metab. 2002, 87, 3864–3866. [Google Scholar] [CrossRef] [PubMed]
  106. Membrez, M.; Ammon-Zufferey, C.; Philippe, D.; Aprikian, O.; Monnard, I.; Macé, K.; Darimont, C. Interleukin-18 protein level is upregulated in adipose tissue of obese mice. Obesity 2009, 17, 393–395. [Google Scholar] [CrossRef]
  107. Valentin-Vega, Y.A.; Kastan, M.B. A new role for ATM: Regulating mitochondrial function and mitophagy. Autophagy 2012, 8, 840–841. [Google Scholar] [CrossRef]
  108. Biton, S.; Ashkenazi, A. NEMO and RIP1 control cell fate in response to extensive DNA damage via TNF-α feedforward signaling. Cell 2011, 145, 92–103. [Google Scholar] [CrossRef]
  109. Ching, J.K.; Spears, L.D.; Armon, J.L.; Renth, A.L.; Andrisse, S.; Collins, R.L.t.; Fisher, J.S. Impaired insulin-stimulated glucose transport in ATM-deficient mouse skeletal muscle. Appl. Physiol. Nutr. Metab. = Physiol. Appl. Nutr. Metab. 2013, 38, 589–596. [Google Scholar] [CrossRef]
  110. Suzuki, A.; Kusakai, G.; Kishimoto, A.; Shimojo, Y.; Ogura, T.; Lavin, M.F.; Esumi, H. IGF-1 phosphorylates AMPK-alpha subunit in ATM-dependent and LKB1-independent manner. Biochem. Biophys. Res. Commun. 2004, 324, 986–992. [Google Scholar] [CrossRef]
  111. Miles, P.D.; Treuner, K.; Latronica, M.; Olefsky, J.M.; Barlow, C. Impaired insulin secretion in a mouse model of ataxia telangiectasia. Am. J. Physiology. Endocrinol. Metab. 2007, 293, E70–E74. [Google Scholar] [CrossRef] [PubMed]
  112. Barlow, C.; Hirotsune, S.; Paylor, R.; Liyanage, M.; Eckhaus, M.; Collins, F.; Shiloh, Y.; Crawley, J.N.; Ried, T.; Tagle, D.; et al. Atm-deficient mice: A paradigm of ataxia telangiectasia. Cell 1996, 86, 159–171. [Google Scholar] [CrossRef] [PubMed]
  113. Schneider, J.G.; Finck, B.N.; Ren, J.; Standley, K.N.; Takagi, M.; Maclean, K.H.; Bernal-Mizrachi, C.; Muslin, A.J.; Kastan, M.B.; Semenkovich, C.F. ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome. Cell Metab. 2006, 4, 377–389. [Google Scholar] [CrossRef] [PubMed]
  114. Daugherity, E.K.; Balmus, G.; Al Saei, A.; Moore, E.S.; Abi Abdallah, D.; Rogers, A.B.; Weiss, R.S.; Maurer, K.J. The DNA damage checkpoint protein ATM promotes hepatocellular apoptosis and fibrosis in a mouse model of non-alcoholic fatty liver disease. Cell Cycle 2012, 11, 1918–1928. [Google Scholar] [CrossRef] [PubMed]
  115. Blackford, A.N.; Jackson, S.P. ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response. Mol. Cell 2017, 66, 801–817. [Google Scholar] [CrossRef]
  116. Ahrens, M.; Ammerpohl, O.; von Schönfels, W.; Kolarova, J.; Bens, S.; Itzel, T.; Teufel, A.; Herrmann, A.; Brosch, M.; Hinrichsen, H.; et al. DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery. Cell Metab. 2013, 18, 296–302. [Google Scholar] [CrossRef] [PubMed]
  117. Li, L.; Liu, H.; Hu, X.; Huang, Y.; Wang, Y.; He, Y.; Lei, Q. Identification of key genes in non-alcoholic fatty liver disease progression based on bioinformatics analysis. Mol. Med. Rep. 2018, 17, 7708–7720. [Google Scholar] [CrossRef]
  118. Viswanathan, P.; Sharma, Y.; Maisuradze, L.; Tchaikovskaya, T.; Gupta, S. Ataxia telangiectasia mutated pathway disruption affects hepatic DNA and tissue damage in nonalcoholic fatty liver disease. Exp. Mol. Pathol. 2020, 113, 104369. [Google Scholar] [CrossRef]
  119. Morishima, N.; Nakanishi, K. Proplatelet formation in megakaryocytes is associated with endoplasmic reticulum stress. Genes Cells Devoted Mol. Cell. Mech. 2016, 21, 798–806. [Google Scholar] [CrossRef]
  120. Han, J.; Kaufman, R.J. The role of ER stress in lipid metabolism and lipotoxicity. J. Lipid Res. 2016, 57, 1329–1338. [Google Scholar] [CrossRef]
  121. Hoseini, Z.; Sepahvand, F.; Rashidi, B.; Sahebkar, A.; Masoudifar, A.; Mirzaei, H. NLRP3 inflammasome: Its regulation and involvement in atherosclerosis. J. Cell. Physiol. 2018, 233, 2116–2132. [Google Scholar] [CrossRef] [PubMed]
  122. Piccaluga, P.P.; Navari, M.; Visani, A.; Rigotti, F.; Agostinelli, C.; Righi, S.; Diani, E.; Ligozzi, M.; Carelli, M.; Ponti, C.; et al. Interferon gamma inducible protein 16 (IFI16) expression is reduced in mantle cell lymphoma. Heliyon 2019, 5, e02643. [Google Scholar] [CrossRef]
  123. Stadion, M.; Schwerbel, K.; Graja, A.; Baumeier, C.; Rödiger, M.; Jonas, W.; Wolfrum, C.; Staiger, H.; Fritsche, A.; Häring, H.U.; et al. Increased Ifi202b/IFI16 expression stimulates adipogenesis in mice and humans. Diabetologia 2018, 61, 1167–1179. [Google Scholar] [CrossRef] [PubMed]
  124. Trammell, S.A.; Brenner, C. NNMT: A Bad Actor in Fat Makes Good in Liver. Cell Metab. 2015, 22, 200–201. [Google Scholar] [CrossRef] [PubMed]
  125. Roberti, A.; Fernández, A.F.; Fraga, M.F. Nicotinamide N-methyltransferase: At the crossroads between cellular metabolism and epigenetic regulation. Mol. Metab. 2021, 45, 101165. [Google Scholar] [CrossRef] [PubMed]
  126. Komatsu, M.; Kanda, T.; Urai, H.; Kurokochi, A.; Kitahama, R.; Shigaki, S.; Ono, T.; Yukioka, H.; Hasegawa, K.; Tokuyama, H.; et al. NNMT activation can contribute to the development of fatty liver disease by modulating the NAD (+) metabolism. Sci. Rep. 2018, 8, 8637. [Google Scholar] [CrossRef]
  127. Kannt, A.; Pfenninger, A.; Teichert, L.; Tönjes, A.; Dietrich, A.; Schön, M.R.; Klöting, N.; Blüher, M. Association of nicotinamide-N-methyltransferase mRNA expression in human adipose tissue and the plasma concentration of its product, 1-methylnicotinamide, with insulin resistance. Diabetologia 2015, 58, 799–808. [Google Scholar] [CrossRef]
  128. Al-Hakeim, H.K.; Al-Rammahi, D.A.; Al-Dujaili, A.H. IL-6, IL-18, sIL-2R, and TNFα proinflammatory markers in depression and schizophrenia patients who are free of overt inflammation. J. Affect. Disord. 2015, 182, 106–114. [Google Scholar] [CrossRef]
  129. Du, X.; Zou, S.; Yue, Y.; Fang, X.; Wu, Y.; Wu, S.; Wang, H.; Li, Z.; Zhao, X.; Yin, M.; et al. Peripheral Interleukin-18 is negatively correlated with abnormal brain activity in patients with depression: A resting-state fMRI study. BMC Psychiatry 2022, 22, 531. [Google Scholar] [CrossRef]
  130. Corbo, R.M.; Businaro, R.; Scarabino, D. Leukocyte telomere length and plasma interleukin-1β and interleukin-18 levels in mild cognitive impairment and Alzheimer’s disease: New biomarkers for diagnosis and disease progression? Neural Regen. Res. 2021, 16, 1397–1398. [Google Scholar] [CrossRef]
  131. Ojala, J.; Alafuzoff, I.; Herukka, S.K.; van Groen, T.; Tanila, H.; Pirttilä, T. Expression of interleukin-18 is increased in the brains of Alzheimer’s disease patients. Neurobiol. Aging 2009, 30, 198–209. [Google Scholar] [CrossRef] [PubMed]
  132. Motta, M.; Imbesi, R.; Di Rosa, M.; Stivala, F.; Malaguarnera, L. Altered plasma cytokine levels in Alzheimer’s disease: Correlation with the disease progression. Immunol. Lett. 2007, 114, 46–51. [Google Scholar] [CrossRef] [PubMed]
  133. Orhan, F.; Fatouros-Bergman, H.; Schwieler, L.; Cervenka, S.; Flyckt, L.; Sellgren, C.M.; Engberg, G.; Erhardt, S. First-episode psychosis patients display increased plasma IL-18 that correlates with cognitive dysfunction. Schizophr. Res. 2018, 195, 406–408. [Google Scholar] [CrossRef] [PubMed]
  134. Sutinen, E.M.; Pirttilä, T.; Anderson, G.; Salminen, A.; Ojala, J.O. Pro-inflammatory interleukin-18 increases Alzheimer’s disease-associated amyloid-β production in human neuron-like cells. J. Neuroinflamm. 2012, 9, 199. [Google Scholar] [CrossRef] [PubMed]
  135. Ojala, J.O.; Sutinen, E.M.; Salminen, A.; Pirttilä, T. Interleukin-18 increases expression of kinases involved in tau phosphorylation in SH-SY5Y neuroblastoma cells. J. Neuroimmunol. 2008, 205, 86–93. [Google Scholar] [CrossRef] [PubMed]
  136. Yamanishi, K.; Doe, N.; Mukai, K.; Hashimoto, T.; Gamachi, N.; Hata, M.; Watanabe, Y.; Yamanishi, C.; Yagi, H.; Okamura, H.; et al. Acute stress induces severe neural inflammation and overactivation of glucocorticoid signaling in interleukin-18-deficient mice. Transl. Psychiatry 2022, 12, 404. [Google Scholar] [CrossRef] [PubMed]
  137. Herzog, K.H.; Chong, M.J.; Kapsetaki, M.; Morgan, J.I.; McKinnon, P.J. Requirement for Atm in ionizing radiation-induced cell death in the developing central nervous system. Science 1998, 280, 1089–1091. [Google Scholar] [CrossRef]
  138. Chong, M.J.; Murray, M.R.; Gosink, E.C.; Russell, H.R.; Srinivasan, A.; Kapsetaki, M.; Korsmeyer, S.J.; McKinnon, P.J. Atm and Bax cooperate in ionizing radiation-induced apoptosis in the central nervous system. Proc. Natl. Acad. Sci. USA 2000, 97, 889–894. [Google Scholar] [CrossRef]
  139. Lee, Y.; Barnes, D.E.; Lindahl, T.; McKinnon, P.J. Defective neurogenesis resulting from DNA ligase IV deficiency requires Atm. Genes Dev. 2000, 14, 2576–2580. [Google Scholar] [CrossRef]
  140. Allen, D.M.; van Praag, H.; Ray, J.; Weaver, Z.; Winrow, C.J.; Carter, T.A.; Braquet, R.; Harrington, E.; Ried, T.; Brown, K.D.; et al. Ataxia telangiectasia mutated is essential during adult neurogenesis. Genes Dev. 2001, 15, 554–566. [Google Scholar] [CrossRef]
  141. Kajiwara, Y.; McKenzie, A.; Dorr, N.; Gama Sosa, M.A.; Elder, G.; Schmeidler, J.; Dickstein, D.L.; Bozdagi, O.; Zhang, B.; Buxbaum, J.D. The human-specific CASP4 gene product contributes to Alzheimer-related synaptic and behavioural deficits. Hum. Mol. Genet. 2016, 25, 4315–4327. [Google Scholar] [CrossRef] [PubMed]
  142. Hopper, S.; Pavey, G.M.; Gogos, A.; Dean, B. Widespread Changes in Positive Allosteric Modulation of the Muscarinic M1 Receptor in Some Participants With Schizophrenia. Int. J. Neuropsychopharmacol. 2019, 22, 640–650. [Google Scholar] [CrossRef] [PubMed]
  143. Tanaka, S.; Matsunaga, H.; Kimura, M.; Tatsumi, K.; Hidaka, Y.; Takano, T.; Uema, T.; Takeda, M.; Amino, N. Autoantibodies against four kinds of neurotransmitter receptors in psychiatric disorders. J. Neuroimmunol. 2003, 141, 155–164. [Google Scholar] [CrossRef] [PubMed]
  144. Dean, B.; McLeod, M.; Keriakous, D.; McKenzie, J.; Scarr, E. Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol. Psychiatry 2002, 7, 1083–1091. [Google Scholar] [CrossRef] [PubMed]
  145. Yamasaki, M.; Matsui, M.; Watanabe, M. Preferential localization of muscarinic M1 receptor on dendritic shaft and spine of cortical pyramidal cells and its anatomical evidence for volume transmission. J. Neurosci. Off. J. Soc. Neurosci. 2010, 30, 4408–4418. [Google Scholar] [CrossRef]
  146. Levey, A.I. Muscarinic acetylcholine receptor expression in memory circuits: Implications for treatment of Alzheimer disease. Proc. Natl. Acad. Sci. USA 1996, 93, 13541–13546. [Google Scholar] [CrossRef]
  147. Stanco, A.; Pla, R.; Vogt, D.; Chen, Y.; Mandal, S.; Walker, J.; Hunt, R.F.; Lindtner, S.; Erdman, C.A.; Pieper, A.A.; et al. NPAS1 represses the generation of specific subtypes of cortical interneurons. Neuron 2014, 84, 940–953. [Google Scholar] [CrossRef]
  148. Winden, K.D.; Oldham, M.C.; Mirnics, K.; Ebert, P.J.; Swan, C.H.; Levitt, P.; Rubenstein, J.L.; Horvath, S.; Geschwind, D.H. The organization of the transcriptional network in specific neuronal classes. Mol. Syst. Biol. 2009, 5, 291. [Google Scholar] [CrossRef]
  149. Morais-Silva, G.; Nam, H.; Campbell, R.R.; Basu, M.; Pagliusi, M.; Fox, M.E.; Chan, S.; Iñiguez, S.D.; Ament, S.; Marin, M.T.; et al. Molecular, circuit, and stress response characterization of Ventral Pallidum Npas1-neurons. bioRxiv 2022. [Google Scholar] [CrossRef]
  150. Kocinaj, A.; Chaudhury, T.; Uddin, M.S.; Junaid, R.R.; Ramsden, D.B.; Hondhamuni, G.; Klamt, F.; Parsons, L.; Parsons, R.B. High Expression of Nicotinamide N-Methyltransferase in Patients with Sporadic Alzheimer’s Disease. Mol. Neurobiol. 2021, 58, 1769–1781. [Google Scholar] [CrossRef]
  151. Bromberg, A.; Lerer, E.; Udawela, M.; Scarr, E.; Dean, B.; Belmaker, R.H.; Ebstein, R.; Agam, G. Nicotinamide-N-methyltransferase (NNMT) in schizophrenia: Genetic association and decreased frontal cortex mRNA levels. Int. J. Neuropsychopharmacol. 2012, 15, 727–737. [Google Scholar] [CrossRef] [PubMed]
  152. Hu, Q.; Liu, F.; Yang, L.; Fang, Z.; He, J.; Wang, W.; You, P. Lower serum nicotinamide N-methyltransferase levels in patients with bipolar disorder during acute episodes compared to healthy controls: A cross-sectional study. BMC Psychiatry 2020, 20, 33. [Google Scholar] [CrossRef] [PubMed]
Ijms 24 17170 g001
Figure 1. Ingenuity pathway analysis (IPA) diagram showing direct and indirect networks among interleukin (IL)18, its receptor (Il18r), and other differentially expressed genes common to liver, brown adipose tissue, and brain in Il18−/− mice. Only Casp4 was predicted to have a direct interaction with IL18.
Figure 1. Ingenuity pathway analysis (IPA) diagram showing direct and indirect networks among interleukin (IL)18, its receptor (Il18r), and other differentially expressed genes common to liver, brown adipose tissue, and brain in Il18−/− mice. Only Casp4 was predicted to have a direct interaction with IL18.
Ijms 24 17170 g001
Table 1. Cancers and related genes with differential expression in liver, brown adipose tissue, and brain under IL18 deficiency.
Table 1. Cancers and related genes with differential expression in liver, brown adipose tissue, and brain under IL18 deficiency.
SymbolEntrez Gene NameCancer
Down-regulated genes
Nxpe4neurexophilin and PC-esterase domain family member 4colon cancer adenocarcinoma, carcinoma, melanoma
Ifi16interferon gamma inducible protein 16colorectal cancer, hepatocellular carcinoma
Ccnd1cyclin D1tongue squamous cell carcinoma
Nnmtnicotinamide N-methyltransferaseprostate cancer
Tmem25transmembrane protein 25breast cancer, colon cancer
Rps25ribosomal protein S25colon rectal cancer, adenocarcinoma, T-cell leukemia
Ppcdcphosphopantothenoylcysteine decarboxylaseendometrioid carcinoma, melanoma
Axin2axin 2colorectal cancer, liver cancer, gastric cancer
Lrrc8eleucine rich repeat containing 8 VRAC subunit Ebreast cancer
AtmATM serine/threonine kinasepancreatic cancer
Samsn1SAM domain, SH3 domain and nuclear localization signals 1lung cancer, myeloma, gastric cancer, glioblastoma, HCC
Ly6alymphocyte antigen 6 complex, locus Atumor progression
Casp4caspase 4lung cancer, gastric cancer, esophageal squamous cell carcinoma
Up-regulated genes
C11orf71chromosome 11 open reading frame 71N.A.
Wscd1WSC domain containing 1N.A.
Npas1neuronal PAS domain protein 1alveolar rhabdomyosarcoma, soft tissue sarcoma cancer
Hmbshydroxymethylbilane synthaseN.A.
Or10ad1olfactory receptor family 10 subfamily AD member 1carcinoma, melanoma
Klf13Kruppel like factor 13oral cancer, pancreatic cancer, prostate cancer, colorectal cancer, oral squamous cell carcinoma
Mical1microtubule associated monooxygenase, calponin and LIM domain containing 1N.A.
Tmem267transmembrane protein 267liver cancer, colon caner
Chrm1cholinergic receptor muscarinic 1prostate cancer, pancreatic tumor
Nntnicotinamide nucleotide transhydrogenasegastric cancer, adrenocortical carcinoma, lung tumor
Erdr1erythroid differentiation regulator 1melanoma, gastric cancers, leukemia cell cancer
N.A., not available.
Table 2. Glucose and lipid metabolism-related genes with differential expression in liver, brown adipose tissue, and brain under IL18 deficiency.
Table 2. Glucose and lipid metabolism-related genes with differential expression in liver, brown adipose tissue, and brain under IL18 deficiency.
SymbolEntrez Gene NameFunction
Down-regulated genes
Ifi16interferon gamma inducible protein 16Glucose metabolism
Ccnd1cyclin D1Glucose metabolism, lipid metabolism
Nnmtnicotinamide N-methyltransferaseGlucose metabolism
AtmATM serine/threonine kinaseGlucose metabolism, lipid metabolism
Casp4caspase 4Glucose metabolism
Up-regulated genes
Hmbshydroxymethylbilane synthaseGlucose metabolism
Chrm1cholinergic receptor muscarinic 1Glucose metabolism, lipid metabolism
Table 3. Functions and diseases of psychiatric disorder-related genes with differential expression in liver, brown adipose tissue, and brain under IL18 deficiency.
Table 3. Functions and diseases of psychiatric disorder-related genes with differential expression in liver, brown adipose tissue, and brain under IL18 deficiency.
SymbolEntrez Gene NameFunction and Diseases
Down-regulated genes
Nnmtnicotinamide N-methyltransferasePsychological disorders
AtmATM serine/threonine kinaseLearning, cognitive impairment
Casp4caspase 4Dementia, Alzheimer’s disease
Up-regulated genes
Npas1neuronal PAS domain protein 1Learning, memory
Chrm1cholinergic receptor muscarinic 1Major depressive disorder, learning, memory, dementia, cognitive impairment, Alzheimer’s disease, psychological disorders
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Yamanishi, K.; Hata, M.; Gamachi, N.; Watanabe, Y.; Yamanishi, C.; Okamura, H.; Matsunaga, H. Molecular Mechanisms of IL18 in Disease. Int. J. Mol. Sci. 2023, 24, 17170. https://doi.org/10.3390/ijms242417170

AMA Style

Yamanishi K, Hata M, Gamachi N, Watanabe Y, Yamanishi C, Okamura H, Matsunaga H. Molecular Mechanisms of IL18 in Disease. International Journal of Molecular Sciences. 2023; 24(24):17170. https://doi.org/10.3390/ijms242417170

Chicago/Turabian Style

Yamanishi, Kyosuke, Masaki Hata, Naomi Gamachi, Yuko Watanabe, Chiaki Yamanishi, Haruki Okamura, and Hisato Matsunaga. 2023. "Molecular Mechanisms of IL18 in Disease" International Journal of Molecular Sciences 24, no. 24: 17170. https://doi.org/10.3390/ijms242417170

APA Style

Yamanishi, K., Hata, M., Gamachi, N., Watanabe, Y., Yamanishi, C., Okamura, H., & Matsunaga, H. (2023). Molecular Mechanisms of IL18 in Disease. International Journal of Molecular Sciences, 24(24), 17170. https://doi.org/10.3390/ijms242417170

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