Interleukin (IL)-18, structurally similar to IL-1β, is a member of IL-1 superfamily of cytokines. This cytokine, which is expressed by many human lymphoid and nonlymphoid cells, has an important role in inflammatory processes. The main function of IL-18 is mediated through induction of interferon-γ (IFN-γ) secretion from T helper (Th1) cells. This cytokine synergistically with IL-12 contributes to Th1 differentiation and, therefore, is important in host defense mechanisms against intracellular bacteria, viruses, and fungi. Recent evidences showing the involvement of IL-18 in Th2 differentiation and ultimately IgE production from B cells have shed a new insight on the dual effects of IL-18 on Th1 and Th2 inflammatory responses. IL-18 in combination with IL-12 can activate cytotoxic T cells (CTLs), as well as natural killer (NK) cells, to produce IFN-γ and, therefore, may contribute to tumor immunity. The biological activity of IL-18 is not limited to these cells, but it also plays a role in development of Th17 cell responses. IL-18 synergistically with IL-23 can induce IL-17 secretion from Th17 cells. The diverse biological activity of IL-18 on T-cell subsets and other immune cells has made this cytokine a good target for investigating its role in various inflammatory-based diseases. Lately, the discovery of IL-18 binding protein (IL-18BP), a physiological inhibitor of IL-18 and a hallmark of IL-18 biology, made this cytokine an attractive target for studying its pros and cons in the treatment of various diseases. In recent years, the biology, genetics, and pathological role of IL-18 have been studied in a number of diseases. In this article, we aimed to present an updated review on these aspects regarding the contribution of IL-18 to important diseases such as cancer, autoimmunity, and inflammatory-mediated conditions including allergic diseases, metabolic syndrome, and atherosclerosis. Emerging data indicating prognostic, diagnostic, and therapeutic features of IL-18 and its related molecules will also be discussed.

Interleukin-18: a regulator of cancer and autoimmune diseases

Prostate cancer is a highly prevalent form of cancer that is usually slow-developing and benign Due to its high prevalence, it is, however, still the second most common cause of death by cancer in men in the West The higher prevalence of prostate cancer in the West might be due to elevated inflammation from metabolic syndrome or associated comorbidities NF-κB activation and many other signals associated with inflammation are known to contribute to prostate cancer malignancy Inflammatory signals have also been associated with the development of castration resistance and resistance against other androgen depletion strategies, which is a major therapeutic challenge Here, we review the role of inflammation and its link with androgen signaling in prostate cancer We further describe the role of NF-κB in prostate cancer cell survival and proliferation, major NF-κB signaling pathways in prostate cancer, and the crosstalk between NF-κB and androgen receptor signaling Several NF-κB-induced risk factors in prostate cancer and their potential for therapeutic targeting in the clinic are described A better understanding of the inflammatory mechanisms that control the development of prostate cancer and resistance to androgen-deprivation therapy will eventually lead to novel treatment options for patients

https://www.mdpi.com/2073-4409/7/9/122/pdf

Inflammation and NF-κB Signaling in Prostate Cancer: Mechanisms and Clinical Implications.

Genetic variation: effect on prostate cancer

Purpose: Increasing investigations have been performed on the association of -607C/A polymorphism in Interleukin-18 (IL-18) gene promoter with cancer risk and have yielded conflicting results. To derive a more precise estimation of the association, we performed an updated meta-analysis of all eligible studies. Methods: We searched all eligible studies by using PubMed, MEDLINE, EMBASE, and China National Knowledge Infrastructure (CNKI) databases. The odds ratios (ORs) were pooled by the fixed-effects/random-effects model in STATA 12.0 software. Results: This meta-analysis included 29 studies with 6,026 cases and 6,476 controls. Overall, significantly in creased cancer risk was observed (A vs C: OR=1.10, 95% CI: 1.01,1.19, Pheterogeneity=0.001; AA vs CC: OR=1.17, 95% CI: 1.01,1.37, Pheterogeneity=0.007; CA vs CC: OR =1.15, 95% CI: 1.05,1.25, Pheterogeneity=0.152; AA/CA vs CC: OR =1.17, 95% CI: 1.06,1.31, Pheterogeneity=0.042). In subgroup analyses based on ethnicity, the results suggested a significant ly increased risk of cancer in Asian population (CA vs CC: OR =1.11, 95% CI: 1.00-1.24, Pheterogeneity=0.353; AA/CA vs CC: OR =1.14, 95% CI: 1.02-1.29, Pheterogeneity=0.081) and in Mixed population (A vs C: OR=1.72, 95% CI: 1.22-2.43, Pheterogeneity=NA; AA vs CC: OR=2.84, 95% CI: 1.43-5.64, Pheterogeneity=NA; AA vs CC/CA: OR =2.43, 95% CI: 1.344.42, Pheterogeneity=NA; AA/CA vs CC: OR =1.69, 95% CI: 1.00-2.85, Pheterogeneity=NA); however, no significant asso ciation was found in Caucasian or African populations. In the subgroup analysis by cancer type we found a significantly increased susceptibility to breast cancer (A vs C: OR =1.33, 95% CI: 1.00-1.75, Pheterogeneity=0.155; AA vs CC: OR =1.80, 95% CI: 1.02-3.21, Pheterogeneity=0.162; AA/CA vs CC: OR =1.33, 95% CI: 1.00-1.78, Pheterogeneity=0.546), nasopharyngeal carcinoma (A vs C: OR =1.16, 95% CI: 1.01-1.32, Pheterogeneity=0.921; AA vs CC: OR =1.34, 95% CI: 1.02-1.75, Pheterogeneity=0.863; CA vs. CC: OR=1.36, 95% CI: 1.08-1.70, Pheterogeneity=0.824; AA/CA vs CC: OR =1.35, 95% CI: 1.091.68, Pheterogeneity=0.904), and esophageal cancer (CA vs CC: OR=1.37, 95% CI: 1.04-1.80, Pheterogeneity=0.528; AA/CA vs CC: OR =1.29, 95% CI: 1.00-1.66, Pheterogeneity=0.700). Conclusions: The current meta-analysis suggests that the -607C/A polymorphism in IL-18 gene promoter is associated with a significantly increased risk of cancer, especially of breast cancer, nasopharyngeal carcinoma and esophageal cancer and in Asian and Mixed populations. More studies with diverse ethnic groups, larger sample size, and well con trolled confounding factors are warranted to further investigate the association. Summary

Increased cancer risk associated with the -607C/A polymorphism in interleukin-18 gene promoter: an updated meta-analysis including 12,502 subjects.

To investigate the potential role of interleukin-18 (IL-18) in immunomodulation during tumorigenesis of esophageal carcinoma and elucidate the underlying molecular mechanism, we employed IL-18 knockout mice for this purpose. Carcinogen 4-nitroquinoline 1-oxide (4NQO) was administrated in drinking water to induce occurrence of esophageal squamous cell carcinoma (ESCC). T cell activation as indicated by the surface CD molecules was analyzed with flow cytometry. The serous content of interferon-γ (IFN-γ) along with other cytokines was determined by inflammatory human cytokine cytometric bead array. The cytotoxicity assay was performed by co-culture of tumor cells with immune cells and relative cell viability was determined by lactate dehydrogenase (LDH) assay. Apoptotic cells were stained with Annexin-V/propidium iodide (PI) and analyzed by flow cytometry. Cell proliferation was measured with Cell Counting Kit-8 (CCK-8) assay. Our data demonstrated that deficiency of IL-18 promoted the progression and development of 4NQO-induced ESCC. Loss of IL-18 suppressed the activation of T cells in the esophagus. Deficiency of IL-18 inhibited the IFN-γ production by CD8+ T cells and natural killer (NK) cells. Absence of IL-18 inhibited the cytotoxicity of CD8+ T cells and NK cell in vitro. Moreover, deficiency of IL-18 promoted the apoptosis of CD8+ T cells and inhibited the proliferation of CD8+ T cells in vitro. Our data elucidated the immunomodulatory role of IL-18 during tumorigenesis of ESCC, whose deficiency compromised antitumor immunity and contributed to immune escape of esophageal carcinoma. Our results also indicated the therapeutic potential of exogenous IL-18 against ESCC, which warrants further investigations.

Deficiency of IL-18 Aggravates Esophageal Carcinoma Through Inhibiting IFN-γ Production by CD8+T Cells and NK Cells.

Interleukin-18 (IL-18) has been implicated in a wide variety of cellular functions that affect the biological response to tumors However, there is insufficient evidence to prove that IL-18 gene variants are associated with risk of prostate cancer We examined a possible association between two promoter polymorphisms, -137G/C (rs187238) and -607C/A (rs1946518), in the IL-18 gene and prostate cancer occurrence and prognosis in Han Chinese We used a high-resolution melting method to genotype these two polymorphisms in 375 Chinese Han patients with prostate cancer and in 400 age-matched healthy controls A hundred and eighty-one prostate cancer patients who had been receiving androgen deprivation therapy, including operational and medical castration, were enrolled to follow-up in this study Carriers of the GG genotype of the -137G/ C polymorphism had a 2165-times higher risk of prostate cancer progression than carriers of GC [95% confidence interval (CI) = 1270-3687] Patients with the GG genotype at clinical stages III and IV also had significantly lower rates of progression-free survival (relative risk = 2174, 95%CI = 1211-3906) However, we found no significant association of genotype or allele distributions of these two polymorphisms with occurrence of prostate cancer We conclude that there is evidence that the IL-18 gene promoter polymorphism -137G/ C influences the prognosis of prostate cancer patients in androgen deprivation therapy, although neither of the two SNPs contributes to prostate cancer development

https://www.funpecrp.com.br/gmr/year2013/vol12-1/pdf/gmr1966.pdf

Effect of IL-18 gene promoter polymorphisms on prostate cancer occurrence and prognosis in Han Chinese population.

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Effect of IL-18 gene promoter polymorphisms on prostate cancer occurrence and prognosis in Han Chinese population.