IL18

Gene Summary

Gene:IL18; interleukin 18
Aliases: IGIF, IL-18, IL-1g, IL1F4
Location:11q23.1
Summary:The protein encoded by this gene is a proinflammatory cytokine that augments natural killer cell activity in spleen cells, and stimulates interferon gamma production in T-helper type I cells. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Aug 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:interleukin-18
Source:NCBIAccessed: 31 August, 2019

Ontology:
What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Contents

Gene Summary

Cancer Overview

Specific Cancers (6)

Useful Links

Latest Publications
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Breast CancerIL18 and Breast Cancer View Publications17
Ovarian CancerIL18 and Ovarian Cancer View Publications8
Skin CancerIL18 and Skin Cancer View Publications8
MelanomaIL18 and Melanoma View Publications8
Prostate CancerIL18 and Prostate Cancer View Publications7
Lung Cancer, Small CellIL18 and Small Cell Lung Cancer View Publications1
Cervical CancerIL18 and Cervical Cancer View Publications6

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: IL18 (cancer-related)

Chang WS, Shen TC, Yeh WL, et al.
Contribution of Inflammatory Cytokine Interleukin-18 Genotypes to Renal Cell Carcinoma.
Int J Mol Sci. 2019; 20(7) [PubMed] Free Access to Full Article Related Publications
Interleukin-18 (
Related: Kidney Cancer

Haralambiev L, Wien L, Gelbrich N, et al.
Effects of Cold Atmospheric Plasma on the Expression of Chemokines, Growth Factors, TNF Superfamily Members, Interleukins, and Cytokines in Human Osteosarcoma Cells.
Anticancer Res. 2019; 39(1):151-157 [PubMed] Related Publications
BACKGROUND/AIM: Therapeutic options for osteosarcoma (OS) are still limited. Cold atmospheric plasma (CAP) leads to inhibition of tumor growth and metastasis, but underlying mechanisms are not fully understood. The aim of this study was to investigate CAP-induced changes in cytokine expression in OS cells.
MATERIALS AND METHODS: OS cell lines (U2-OS, MNNG/HOS) were treated with CAP and administered to an RT2 Profiler PCR Array (Qiagen, Hilden, Germany) detecting 84 chemokines, growth factors, TNF superfamily members, interleukins, and cytokines.
RESULTS: The analyses showed that 15 factors (C5, CCL5, CNTF, CSF1, CSF3, CXCL1, IL-1A, IL-1B, IL-18, IL-22, IL23A, MSTN, NODAL, TGFβ2, THPO) were induced, but only one factor (VEGFA) was suppressed after CAP treatment.
CONCLUSION: No extensive systemic cell response with presumably far-reaching consequences for neighboring cells was detectable after CAP treatment. Since the antitumoral effect of CAP on OS cells has already been demonstrated, intraoperative treatment with CAP represents a promising and systemic safe option for the therapy of OS.
Related: Cytokines Osteosarcoma

Sato W, Ikeda K, Urano T, et al.
Efp promotes in vitro and in vivo growth of endometrial cancer cells along with the activation of nuclear factor-κB signaling.
PLoS One. 2018; 13(12):e0208351 [PubMed] Free Access to Full Article Related Publications
Endometrial cancer is common among postmenopausal women and its incidence is increasing in developed countries. Considering that >80% of endometrial cancers are assumed to be estrogen-related, higher estrogen exposure will be relevant to tumorigenesis. Therefore, the roles of estrogen target genes will be important to understand the pathophysiological mechanisms. We previously revealed that estrogen-responsive RING finger protein Efp contributes to breast cancer progression through the protein degradation of cell cycle checkpoint 14-3-3σ. We and others also proposed that Efp has tumor-promoting activities in estrogen receptor (ER)-negative cancer cells. In addition, Efp plays a role in type I interferon production by activating antiviral signaling, which provokes nuclear factor-κB (NF-κB) signaling. In the present study, we investigate whether Efp plays a critical role in endometrial cancer biology. We show that siRNA-mediated Efp knockdown represses the proliferation and migration of endometrial cancer ER-positive Ishikawa and ER-negative HEC-1A cells. Efp knockdown increases 14-3-3σ protein levels and decreases the rates proliferative stage cells. Efp siRNA significantly inhibits the in vivo tumor growth of endometrial cancer cells in both subcutaneous and orthotopic xenograft models. Intriguingly, Efp knockdown represses NF-κB-dependent transactivation and transcription of target genes, such as IL6ST and IL18, in endometrial cancer cells. Overall, Efp would exert a tumor-promoting role through modulating NF-κB pathway and 14-3-3σ protein degradation in endometrial cancer regardless of its estrogen receptor status. Our results indicate that Efp could be a potential diagnostic and therapeutic target for endometrial cancer.
Related: Endometrial (Uterus) Cancer Endometrial Cancer Signal Transduction

da Silva WC, Reis EC, Oshiro TM, Pontillo A
Genetics of Inflammasomes.
Exp Suppl. 2018; 108:321-341 [PubMed] Related Publications
Mutations in inflammasome genes are responsible for rare monogenic and polygenic autoinflammatory diseases. On the other side, genetic polymorphisms in the same molecules contribute to the development of common multifactorial diseases (i.e., autoimmune diseases, cardiovascular pathologies, cancer). In this chapter we depicted the current knowledge about inflammasome genetics.
Related: Cancer Prevention and Risk Reduction Polymorphisms

Li N, Wang J, Yu W, et al.
MicroRNA‑146a inhibits the inflammatory responses induced by interleukin‑17A during the infection of Helicobacter pylori.
Mol Med Rep. 2019; 19(2):1388-1395 [PubMed] Related Publications
Helicobacter pylori (H. pylori) infection is the major cause of chronic active gastritis and peptic ulcer disease. Upregulation of IL‑17A is associated with H. pylori infection in the gastric mucosa; however, the factors involved in the regulation of interleukin (IL)‑17A‑induced inflammatory responses in H. pylori‑associated gastritis remain unknown. MicroRNAs (miRNAs) serve as key post‑transcriptional regulators of gene expression and are associated with the H. pylori infection. The present study aimed to analyze the effects of IL‑17A on the expression of miR‑146a upon infection with H. pylori, as well as to identify the possible impact of miR‑146a dysregulation on the inflammatory response in vivo and in vitro. Reverse transcription‑quantitative polymerase chain reaction analysis was used to determine the expression levels of miR‑146a in gastric epithelial cells upon IL‑17A stimulation. The effects of miR‑146a mimics on IL‑17A‑induced inflammatory responses in SGC‑7901 cells were evaluated. The effects of miR‑146a mimics on the expression levels of IL‑1 receptor‑associated kinase 1 (IRAK1) and tumor necrosis factor receptor‑associated factor 6 (TRAF6) upon IL‑17A treatment were analyzed, and the IL‑17A‑stimulated inflammation following the silencing of IRAK1 and TRAF6 was observed. In addition, the correlation between miR‑146a and IL‑17A in human gastric mucosa with H. pylori was examined. The results indicated that IL‑17A‑induced miR‑146a may regulate the inflammatory response during the infection of H. pylori in a nuclear factor‑κB‑dependent manner. Furthermore, the expression of miR‑146a and IL‑17A are positively correlated in human gastric mucosa infected with H. pylori. These data suggested that miR‑146a may serve as a biomarker or therapeutic target in gastritis therapy.
Related: MicroRNAs Stomach Cancer Gastric Cancer

Juric V, O'Sullivan C, Stefanutti E, et al.
MMP-9 inhibition promotes anti-tumor immunity through disruption of biochemical and physical barriers to T-cell trafficking to tumors.
PLoS One. 2018; 13(11):e0207255 [PubMed] Free Access to Full Article Related Publications
Matrix metalloproteinase-9 (MMP-9), whose expression is frequently dysregulated in cancer, promotes tumor growth, invasion, and metastasis by multiple mechanisms, including extracellular matrix remodeling and growth-factor and cytokine activation. We developed a monoclonal antibody against murine MMP-9, which we found decreased growth of established primary tumors in an orthotopic model of HER2-driven breast cancer (HC11-NeuT) in immunocompetent mice. RNA sequencing (RNAseq) profiling of NeuT tumors and additional mouse model tumors revealed that anti-MMP-9 treatment resulted in upregulation of immune signature pathways associated with cytotoxic T-cell response. As there is a need to boost the low response rates observed with anti-PDL1 antibody treatment in the clinical setting, we assessed the potential of anti-MMP-9 to improve T-cell response to immune checkpoint inhibitor anti-PDL1 in NeuT tumors. Anti-MMP-9 and anti-PDL1 cotreatment reduced T-cell receptor (TCR) clonality and increased TCR diversity, as detected by TCR sequencing of NeuT tumors. Flow cytometry analyses of tumors showed that the combination treatment increased the frequency of CD3+ T cells, including memory/effector CD4 and CD8 T cells, but not regulatory T cells, among tumor-infiltrating leukocytes. Moreover, in vitro enzymatic assays corroborated that MMP-9 cleaves key T-cell chemoattractant CXC receptor 3 ligands (CXC ligand [CXCL] 9, CXCL10, and CXCL11) and renders them inactive in T-cell migration assays. Consistent with our in vitro experiments, analysis of NeuT tumor protein lysates showed that anti-MMP-9 treatment increases expression of CXCL10 and other T cell-stimulating factors, such as interleukin (IL)-12p70 and IL-18. We show that inhibition of MMP-9, a key component of the tumor-promoting and immune-suppressive myeloid inflammatory milieu, increases T-helper cell 1 type cytokines, trafficking of effector/memory T cells into tumors, and intratumoral T-cell diversity.
Related: MMP9: matrix metallopeptidase 9

Zhao X, Hua M, Yan S, et al.
The Genetic Polymorphisms of NLRP3 Inflammasome Associated with T Helper Cells in Patients with Multiple Myeloma.
J Immunol Res. 2018; 2018:7569809 [PubMed] Free Access to Full Article Related Publications
The pathogenesis of multiple myeloma (MM) remains unclear and the NLRP3 inflammasome has been more and more recognized in the progression of many diseases. To investigate the role of the NLRP3 inflammasome in MM, we determined the genetic polymorphisms and expression of NLRP3 inflammasome-related genes (IL-1
Related: Myeloma Myeloma - Molecular Biology

Ding Q, Shen L, Nie X, et al.
MiR-223-3p overexpression inhibits cell proliferation and migration by regulating inflammation-associated cytokines in glioblastomas.
Pathol Res Pract. 2018; 214(9):1330-1339 [PubMed] Related Publications
Glioblastoma(GBM) is most common brain tumor in adults. Currently standard treatments have limited effect to increase the survival, because there are still largely unclear mechanisms in glioblastoma development. miR-223 was involved in various types of cancer, however, the function of miR-223-3p in GBM was still unclear. In our study, real-time PCR was performed to exam the expression level of miR-223-3p and NLRP3 (Nucleotide-binding oligomerization domain(NOD)-like receptor family PYRIN domain containing-3) in GBM tissues. Following that, mimic or inhibitor of miR-223-3p were used to modulate miR-223-3p expression in GBM cell lines respectively. Then, we analyzed cell proliferation and migration by cell counting kit and transwell assay. Further, western blot was performed to detect several inflammation-associated cytokines level in GBM cell lines. We found that miR-223-3p was decreased but NLRP3 was increased in GBM tissues. Treatment with miR-223-3p mimic inhibits cell proliferation and migration via decreasing several inflammation-associated cytokines, including interleukin-1β (IL-1β), monocyte chemoattractant protein-1 (MCP-1), IL-8 and IL-18. Importantly, these effects induced by miR-223-3p could be attenuated by NLRP3 overexpression, which was considered as one of target genes of miR-223-3p. In conclusion, these results indicated that miR-223-3p might act as a suppressor and a potential therapy target of GBM.
Related: Cytokines MicroRNAs

Qiao X, Xu D, Sun D, et al.
Association analysis of interleukin-18 gene promoter region polymorphisms and susceptibility to sporadic breast cancer in Chinese Han women.
J Clin Lab Anal. 2018; 32(9):e22591 [PubMed] Related Publications
BACKGROUND: Interleukin-18-137G/C, -607G/T polymorphisms play multiple roles in various cancers. However, studies focused on its involvement in breast cancer remain controversial, and no study has taken the interaction between interleukin-18 (IL-18) gene polymorphism and body mass index (BMI), menopause into consideration. The study investigated the association between IL-18-137, -607 polymorphisms and risk of breast cancer and a possible interaction between the 2 single nucleotide polymorphisms (SNPs) and BMI, menopause in Chinese Han woman.
METHODS: A total of 488 participants, including 178 patients with breast cancer, 150 patients with benign breast disease and 160 healthy controls were recruited for this study. Polymerase chain reaction (PCR)-direct sequencing technology was used to identify the genotypes.
RESULTS: 137 G/C genotype can decrease the risk of breast cancer (OR = 0.54, 95% CI: 0.31-0.93; P = .025). In benign group, subjects with G/C genotype of IL-18-137G/C polymorphism had a 1.89-fold increased risk of developing breast cancer (95% CI = 1.05-3.41; P = .032). Among postmenopausal subjects, people with G/T genotype of IL-18-607 polymorphism had a 7.97-fold increased risk of lymph node metastasis compared with those with T/T homozygotes (95% CI = 1.95-32.65; P = .0045). Among Overweight and obese patients with breast cancer (BMI ≥ 24), people with G/T genotype of IL-18-607 polymorphism had a 5.45-fold increased risk of lymph node metastasis compared with those with T/T homozygotes (95% CI = 1.74-17.06; P = .034).
CONCLUSIONS: IL-18-137 G/C genotype may be a protective factor for healthy group, but a risk factor for benign group. IL-18-607 G/T genotype have an interaction with menopausal and BMI. The synergetic effect can further increase the risk of lymph node metastasis for breast cancer patients.
Related: Breast Cancer

Guan X, Liu Z, Zhang J, Jin X
Myeloid-derived suppressor cell accumulation in renal cell carcinoma is correlated with CCL2, IL-17 and IL-18 expression in blood and tumors.
Adv Clin Exp Med. 2018; 27(7):947-953 [PubMed] Related Publications
BACKGROUND: Myeloid-derived suppressor cells (MDSC) play an important role in tumor-mediated immune evasion. Levels of MDSC in peripheral blood are increased in patients with cancer, correlating with cancer stage and outcome. Studies have confirmed the associations between MDSC and various cytokines in the peripheral blood of murine and human cancer hosts. However, little is known about the association between parenchymal MDSC subsets and cytokines, or the mechanism drawing MDSC into tumor parenchyma.
OBJECTIVES: The aim of this study was to analyze the correlation between MDSC subsets and tumor grade as well as stage in renal cell carcinoma (RCC) patients. The expression of chemokine (C-C motif) ligand 2 (CCL2), interleukin 17 (IL-17) and interleukin 18 (IL-18) in the peripheral blood and parenchyma of RCC patients was also detected to explore its correlation with MDSC accumulation.
MATERIAL AND METHODS: Total MDSC, granulocytic MDSC (G-MDSC), monocytic MDSC (M-MDSC), and immature MDSC (I-MDSC) from the blood and parenchyma were isolated and analyzed by flow cytometry. Cytokines were detected by the enzyme-linked immunosorbent assay (ELISA), real-time polymerase chain reaction (PCR) and western blot in blood and tumors.
RESULTS: Parenchymal levels of MDSC had a positive correlation with levels of CCL2, IL-17, and IL-18, suggesting these cytokines may attract MDSC into the parenchyma. Moreover, peripheral total MDSC, G-MDSC and I-MDSC were shown to correlate with tumor grade and stage. Gene and protein expression of CCL2, IL-17, and IL-18 was significantly increased in blood and tumors of RCC patients.
CONCLUSIONS: Our study has provided potential new targets for the risk stratification of patients with limited stages of renal carcinoma, in addition to elucidating a possible association between MDSC subsets and cytokine-induced migration into the tumor tissue.
Related: Kidney Cancer

Zhu X, Wu T, Chi Y, et al.
Pyroptosis induced by enterovirus A71 infection in cultured human neuroblastoma cells.
Virology. 2018; 521:69-76 [PubMed] Related Publications
Enterovirus A71 (EV-A71) infection can cause hand, foot and mouth disease (HFMD), and even fatal meningoencephalitis. Unfortunately, there is currently no effective treatment for EV-A71 infection due to the lack of understanding of the mechanism of neurological diseases. In this study, we employed SH-SY5Y human neuroblastoma cells to explore the roles of caspase-1 in neuropathogenesis. The expression and activity of caspase-1 were analyzed. The potential immuneconsequences mediated by caspase-1 including cell death, lysis, DNA degradation, and secretion of pro-inflammatory were also examined. We found the gene expression levels of caspase-1, IL-1β, IL-18 and active caspase-1 were markedly increased in the SH-SY5Y cells at 48 h post EV-A71 infection. The cell death, lysis, and DNA degradation were also increased during infection, which could be significantly alleviated by caspase-1 inhibition. These observations provided additional experimental evidence supporting caspase-1-mediated pyroptosis as a novel pathway of inflammatory programmed cell death.
Related: Neuroblastoma

Lacher MD, Bauer G, Fury B, et al.
SV-BR-1-GM, a Clinically Effective GM-CSF-Secreting Breast Cancer Cell Line, Expresses an Immune Signature and Directly Activates CD4
Front Immunol. 2018; 9:776 [PubMed] Free Access to Full Article Related Publications
Targeted cancer immunotherapy with irradiated, granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting, allogeneic cancer cell lines has been an effective approach to reduce tumor burden in several patients. It is generally assumed that to be effective, these cell lines need to express immunogenic antigens coexpressed in patient tumor cells, and antigen-presenting cells need to take up such antigens then present them to patient T cells. We have previously reported that, in a phase I pilot study (ClinicalTrials.gov NCT00095862), a subject with stage IV breast cancer experienced substantial regression of breast, lung, and brain lesions following inoculation with clinical formulations of SV-BR-1-GM, a GM-CSF-secreting breast tumor cell line. To identify diagnostic features permitting the prospective identification of patients likely to benefit from SV-BR-1-GM, we conducted a molecular analysis of the SV-BR-1-GM cell line and of patient-derived blood, as well as a tumor specimen. Compared to normal human breast cells, SV-BR-1-GM cells overexpress genes encoding tumor-associated antigens (TAAs) such as PRAME, a cancer/testis antigen. Curiously, despite its presumptive breast epithelial origin, the cell line expresses major histocompatibility complex (MHC) class II genes (
Related: Breast Cancer

Qi Y, Zhao W, Li M, et al.
High C-X-C motif chemokine 5 expression is associated with malignant phenotypes of prostate cancer cells via autocrine and paracrine pathways.
Int J Oncol. 2018; 53(1):358-370 [PubMed] Related Publications
The present study aimed to examine the effects and mechanisms of exogenous C-X-C motif chemokine 5 (CXCL5) and lentiviral CXCL5 overexpression on the regulation of malignant behaviors of prostate cancer cells in vitro and in a nude mouse xenograft model. The expression levels of CXCL5 and a number of tumor-related genes were assessed by using semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), western blotting, ELISA, or immunohistochemistry in normal and cancerous prostate cells and tissues. Cell proliferation, colony formation, and Transwell assays were performed to determine the effects of exogenous, autocrine, and paracrine CXCL5 on prostate cancer cell proliferative and migratory capacity. The results indicated that CXCL5 expression was upregulated in PC‑3 and DU145 prostate cancer cells, in WPMY‑1 normal prostate stromal cells, and in RWPE‑1 prostate epithelial cells, as well as in prostate cancer tissue specimens. Exogenous CXCL5 exposure resulted in increase in prostate cancer cell proliferation, colony formation, and migration. In cells transfected with a CXCL5 overexpression vector, in cells cultured in conditioned medium from CXCL5-overexpressing WPMY cells, and in cells co-cultured with CXCL5‑OE WPMY cells prostate cancer cell malignant phenotypes were induced in an autocrine/paracrine fashion in vitro; similar results were observed in nude mouse xenografts. CXCL5 overexpression also regulated expression of tumor-related genes, including BAX, N-Myc downstream-regulated gene 3, extracellular signal-regulated kinase 1/2, C-X-C chemokine receptor type 2, interleukin 18, Bcl‑2, and caspase‑3. These data demonstrated that CXCL5 expression was upregulated in prostate cancer tissues and that exogenous CXCL5 protein exposure or CXCL5 overexpression promoted malignant phenotypes of prostate cancer cells in vitro and in vivo.
Related: Prostate Cancer Signal Transduction

Kong YH, Xu SP
Salidroside prevents skin carcinogenesis induced by DMBA/TPA in a mouse model through suppression of inflammation and promotion of apoptosis.
Oncol Rep. 2018; 39(6):2513-2526 [PubMed] Free Access to Full Article Related Publications
Salidroside (SR) is a main component of Rhodiola rosea L. and exhibits a variety of pharmacologic properties. The present study was carried out to explore the potential effect of SR against skin cancer induced by 7,12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13‑acetate (TPA) in female Institute for Cancer Research (ICR) mice and to reveal the underlying molecular targets regulated by SR. The mice were randomly divided into 4 groups: control, DMBA/TPA, DMBA/TPA+SR (20 mg/kg) and DMBA/TPA+SR (40 mg/kg). SR was administered to mice five times a week after DMBA treatments. In our study, we found that SR dose-dependently ameliorated skin cancer incidence and the multiplicity in the animal models by reducing the release of inflammation-related cytokines, including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), interleukin-18 (IL-18), interleukin-6 (IL-6), cyclooxygenase 2 (COX2) and transforming growth factor β-1 (TGF-β1). Suppression of the nuclear factor (NF)-κB signaling pathway by SR was effective to prevent skin carcinogenesis. Furthermore, TUNEL analysis indicated that compared to the DMBA/TPA group, enhanced apoptosis was observed in the DMBA/TPA+SR group. In addition, p53 expression levels were increased by SR in the DMBA/TPA-induced mice. Therefore, SR was effective for inducing apoptosis during skin cancer progression triggered by DMBA/TPA. Consistently, p21, p53 upregulated modulator of apoptosis (PUMA), Bax and caspase-3 were highly induced by SR to enhance the apoptotic response for preventing skin cancer. Moreover, in vitro, we found that SR dramatically reduced the inflammatory response, while enhancing the aoptotic response by blocking NF-κB and activating caspase-3 pathways, respectively. In addition, flow cytometric analysis further confirmed the induction of apoptosis by SR in DMBA-treated cells in vitro. Taken together, the in vivo and in vitro studies illustrated that SR might be a promising compound to reduce skin cancer risk.
Related: Apoptosis Cytokines Skin Cancer TP53

Nakamura K, Kassem S, Cleynen A, et al.
Dysregulated IL-18 Is a Key Driver of Immunosuppression and a Possible Therapeutic Target in the Multiple Myeloma Microenvironment.
Cancer Cell. 2018; 33(4):634-648.e5 [PubMed] Related Publications
Tumor-promoting inflammation and avoiding immune destruction are hallmarks of cancer. Here, we demonstrate that the pro-inflammatory cytokine interleukin (IL)-18 is critically involved in these hallmarks in multiple myeloma (MM). Mice deficient for IL-18 were remarkably protected from Vk
Related: Myeloma Myeloma - Molecular Biology MYC

Vakrakou AG, Boiu S, Ziakas PD, et al.
Systemic activation of NLRP3 inflammasome in patients with severe primary Sjögren's syndrome fueled by inflammagenic DNA accumulations.
J Autoimmun. 2018; 91:23-33 [PubMed] Related Publications
Sjögren's syndrome (SS) patients manifest high cell-free DNA (cf-DNA) levels in serum, associated with impaired DNaseI activity. Undegraded DNA may accumulate in tissues and act as an inflammasome-activating signal. Herein, we investigated the occurrence of aberrant DNA build-up in various biologic compartments of SS patients and its correlation with the activity of NLRP3 and AIM2 inflammasomes. For this purpose, we evaluated sera, PBMC, circulating monocytes and salivary glands (SG) from different SS patient subgroups and controls. We found that SS patients at high risk for lymphoma and those with established lymphoma display high serum cf-DNA levels, substantial extranuclear DNA accumulations in PBMC and SG tissues, a unique NLRP3 inflammasome gene signature in PBMC, and significantly increased serum IL-18 and ASC levels. In these patients, the circulating monocytes manifested NLRP3 inflammasome activation and increased response to NLRP3 stimuli, whereas SG-infiltrating macrophages exhibited signs of NLRP3 activation and pyroptosis. Cell-free nucleic acids isolated from patients' sera competently primed the activation of both NLRP3 and AIM2 inflammasomes in healthy monocytes. SS patients also manifested diminished DNaseI activity in serum and DNaseII expression in PBMC, which inversely correlated with indices of inflammasome activation. DNaseII gene-silencing in healthy monocytes led to cytoplasmic DNA deposition and activation of inflammasome-related genes and of caspase1. Our data reveal the occurrence of systemic NLRP3 inflammasome activation in severe SS, which is associated with widespread extranuclear accumulations of inflammagenic DNA and impaired DNA degradation. These findings can provide novel biomarkers and new therapeutic targets for the management of SS patients with adverse outcomes.

Esmailbeig M, Ghaderi A
Interleukin-18: a regulator of cancer and autoimmune diseases.
Eur Cytokine Netw. 2017; 28(4):127-140 [PubMed] Related Publications
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.
Related: Cytokines Cancer Prevention and Risk Reduction Signal Transduction

Sannino F, Sansone C, Galasso C, et al.
Pseudoalteromonas haloplanktis TAC125 produces 4-hydroxybenzoic acid that induces pyroptosis in human A459 lung adenocarcinoma cells.
Sci Rep. 2018; 8(1):1190 [PubMed] Free Access to Full Article Related Publications
In order to exploit the rich reservoir of marine cold-adapted bacteria as a source of bioactive metabolites, ethyl acetate crude extracts of thirteen polar marine bacteria were tested for their antiproliferative activity on A549 lung epithelial cancer cells. The crude extract from Pseudoalteromonas haloplanktis TAC125 was the most active in inhibiting cell proliferation. Extensive bioassay-guided purification and mass spectrometric characterization allowed the identification of 4-hydroxybenzoic acid (4-HBA) as the molecule responsible for this bioactivity. We further demonstrate that 4-HBA inhibits A549 cancer cell proliferation with an IC
Related: Lung Cancer Signal Transduction

Bakr NM, Awad A, A Moustafa E
Association of genetic variants in the interleukin-18 gene promoter with risk of hepatocellular carcinoma and metastasis in patients with hepatitis C virus infection.
IUBMB Life. 2018; 70(2):165-174 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is a primary malignancy of the liver, characterized by high vascularization and rapid tumor progression. The current case-control study aimed to analyze the influence of -607C/A and -137G/C polymorphisms in the interleukin-18 (IL-18) promoter on the risk of HCC occurrence and metastasis in Egyptian patients infected with hepatitis C virus (HCV). Both genetic variations were genotyped in 279 subjects including HCV patients with and without HCC and unrelated healthy subjects, using the allele-specific polymerase chain reaction (AS-PCR) method. The relationship between clinico-laboratory parameters including serum level of alpha-fetoprotein (AFP) and these polymorphisms was evaluated in HCC patients. The IL-18-607A allele and AA genotype were significantly related to a higher risk of developing HCC when comparing patients with HCC and controls, and were significantly related to a higher risk of metastasis when comparing metastatic and nonmetastatic groups in the Egyptian patients. In contrast, the IL18-137C allele and GC genotype were significantly related to a lower risk of developing HCC when comparing patients with HCC and controls, and HCV patients with and without HCC. A significant association was found between multinodular HCC and IL-18-607AA genotype, while, uninodular HCC was significantly associated with IL-18-137GG genotype. In addition, IL18-607AA and -137GG genotypes showed significant association with higher level of serum AFP. The detection of polymorphisms in the IL-18 promoter, in a combination with an evaluation of level of serum AFP, could be used as a molecular biomarker in the early diagnosis of HCC, which would aid the early management of the disease, thus decreasing the rate of mortality of this disease. © 2018 IUBMB Life, 70(2):165-174, 2018.
Related: Liver Cancer AFP

Meraz IM, Majidi M, Cao X, et al.
TUSC2 Immunogene Therapy Synergizes with Anti-PD-1 through Enhanced Proliferation and Infiltration of Natural Killer Cells in Syngeneic
Cancer Immunol Res. 2018; 6(2):163-177 [PubMed] Free Access to Full Article Related Publications
Expression of the multikinase inhibitor encoded by the tumor suppressor gene
Related: Lung Cancer

Deswaerte V, Nguyen P, West A, et al.
Inflammasome Adaptor ASC Suppresses Apoptosis of Gastric Cancer Cells by an IL18-Mediated Inflammation-Independent Mechanism.
Cancer Res. 2018; 78(5):1293-1307 [PubMed] Related Publications
Inflammasomes are key regulators of innate immunity in chronic inflammatory disorders and autoimmune diseases, but their role in inflammation-associated tumorigenesis remains ill-defined. Here we reveal a protumorigenic role in gastric cancer for the key inflammasome adaptor apoptosis-related speck-like protein containing a CARD (ASC) and its effector cytokine IL18. Genetic ablation of ASC in the
Related: Apoptosis Signal Transduction Stomach Cancer Gastric Cancer

Chmielewski M, Abken H
CAR T Cells Releasing IL-18 Convert to T-Bet
Cell Rep. 2017; 21(11):3205-3219 [PubMed] Related Publications
Adoptive therapy with chimeric antigen receptor (CAR)-redirected T cells has achieved remarkable efficacy in the treatment of hematopoietic malignancies. However, eradicating large solid tumors in advanced stages of the disease remains challenging. We explored augmentation of the anti-tumor immune reaction by establishing an acute inflammatory reaction. Systematic screening indicates that IL-18 polarizes CAR T cells toward T-bet
Related: Lung Cancer Cancer of the Pancreas Pancreatic Cancer

Xiao TT, Li X, Xu Y, Li Y
Significant association of the cytokine variants with head and neck cancer risk: evidence from meta-analysis.
Eur Arch Otorhinolaryngol. 2018; 275(2):483-496 [PubMed] Related Publications
AIM: To evaluate the possible relevance of the IL-18-137 G>C (rs187238), IL-18-607 C>A (rs1946518) and IL-4-590 C>T (rs2243250) polymorphisms to the genetic susceptibility of head and neck cancer.
METHODS: Data were retrieved from PubMed, EMBASE, Web of Science and CNKI databases, and the results were independently analysed by two reviewers using Stata 14.0 software.
RESULTS: After searching for and assessing the literature, a total of thirteen studies involving 2,959 patients newly diagnosed as head and neck cancer and 3,622 controls from healthy donors were analysed. The results suggested that a strong relationship between patients and healthy controls was observed in the IL-18-137 G>C polymorphism in consistence with the result (CC vs. GG + GC: OR = 1.63, P = 0.004; CC vs. GG: OR = 1.82, P = 0.001). When stratified by cancer type, ethnicity and the source of control samples, significant and elevated risks were obtained in the genetic susceptibility to Asian patients with NPC in all genetic models and in those studies using the PCR-RFLP test method. In addition, comparable results were obtained for the IL-18-607 C>A polymorphism, especially for Asian patients with NPC.
CONCLUSIONS: It should be a potential association between IL-18 variants and nasopharyngeal carcinoma. Furthermore, IL-18 gene variants might be considered as a critical role in predicting the occurrence of nasopharyngeal carcinoma in Asian population. However, the IL-4-590 C>T polymorphism does not influence the development of head and neck cancer.
Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology IL4 Nasopharyngeal Cancer

Zhang A, Yu J, Yan S, et al.
The genetic polymorphism and expression profiles of NLRP3 inflammasome in patients with chronic myeloid leukemia.
Hum Immunol. 2018; 79(1):57-62 [PubMed] Related Publications
NLRP3 inflammasome has been recently reported as an important risk factor in the development of cancer. But the relationship between polymorphisms of NLRP3 inflammasome related genes and chronic myeloid leukemia (CML) is rarely reported. Therefore, the aim of the present study was to investigate the association of five genetic polymorphisms (NLRP3, IL-1β, IL-18, CARD8 and NF-κB) in 267 CML patients and 344 healthy controls. We found that the AT genotype of CARD8 (rs2043211) was significantly higher compared to TT genotype in high and intermediate risk CML patients. IL-1β (rs16944) polymorphism in early molecular response at 6 months was marginally different, with more GG and less AA genotype in BCR-ABL
Related: Chronic Myeloid Leukemia (CML) CML - Molecular Biology

Huang CF, Chen L, Li YC, et al.
NLRP3 inflammasome activation promotes inflammation-induced carcinogenesis in head and neck squamous cell carcinoma.
J Exp Clin Cancer Res. 2017; 36(1):116 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: NLRP3 inflammasome acts as a danger signal sensor that triggers and coordinates the inflammatory response. However, the roles of NLRP3 inflammasome in the tumorigenesis and development of cancer stem cells (CSCs) of squamous cell carcinoma of the head and neck (SCCHN) remain ambiguous.
METHODS: In our study, tissue microarrays, ELISA, sphere-forming assay, colony formation assay and Western blot analysis were performed to evaluate the effect of NLRP3 inflammasome on the development of CSCs in human SCCHN tissue specimen, cell lines, and transgenic mouse SCCHN model.
RESULTS: The components of NLRP3 inflammasome, namely, NLRP3, ASC, Caspase-1, and IL-18 were correlated with CSCs markers BMI1, ALDH1 and CD44 in human SCCHN specimens. Moreover, NLRP3, Caspase-1, IL-1β, and IL-18 were highly expressed in SCCHN cell lines. NLRP3 inflammasome activated by LPS and ATP promoted sphere-forming and colony formation capacities along with an upregulation of BMI1, ALDH1 and CD44. In addition, NLRP3 inflammasome blockade by NLRP3 inhibitor MCC950 reduced sphere and colony number, also decreased the expression of BMI1, ALDH1 and CD44 in SCCHN cell lines. Expression of NLRP3, ASC, Caspase-1, IL-1β, IL-18, BMI1, ALDH1 and CD44 was upregulated in Tgfbr1/Pten 2cKO mouse SCCHN model, and NLRP3 inflammasome expression was closely related to those CSCs makers in mice SCCHN. However, MCC950 treatment reduced the expression of NLRP3 inflammasome, CSCs markers BMI1, ALDH1 and CD44 in Tgfbr1/Pten 2cKO mice SCCHN. In addition, blockade of NLRP3 inflammasome can also delayed the tumor-burdened speed in SCCHN mice.
CONCLUSIONS: Our study demonstrates that NLRP3 inflammasome was upregulated and associated with the carcinogenesis and CSCs self-renewal activation in SCCHN. NLRP3 inflammasome can be a potential target in the development of novel approaches for head and neck squamous cell carcinoma therapy.
Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology PTEN

Zhou Q, Sun E, Ling L, et al.
Bioinformatic analysis of computational identified differentially expressed genes in tumor stoma of pregnancy‑associated breast cancer.
Mol Med Rep. 2017; 16(3):3345-3350 [PubMed] Related Publications
The present study aimed to screen the differentially expressed genes (DEGs) in tumor‑associated stroma of pregnancy‑associated breast cancer (PABC). By analyzing Affymetrix microarray data (GSE31192) from the Gene Expression Omnibus database, DEGs between tumor asso-ciated stromal cells and normal stromal cells in PABC were identified. Gene Ontology (GO) function and pathway enrichment analyses for the DEGs were then performed, followed by construction of a protein‑protein interaction (PPI) network. A total of 94 upregulated and 386 downregulated DEGs were identified between tumor associated stromal cells and normal stromal cells in patients with PABC. The upregulated DEGs were primarily enriched in the cytokine‑cytokine receptor interaction pathway and GO terms associated with the immune response, which included the DEGs of interleukin 18 (IL18) and cluster of differentiation 274 (CD274). The downregulated DEGs were primarily involved in GO terms associated with cell surface receptor linked signal transduction and pathways of focal adhesion and pathways in cancer. In the PPI network, nodes of jun proto‑oncogene (JUN), FBJ murine osteosarcoma viral oncogene homolog (FOS), V‑myc avian myelocytomatosis viral oncogene homolog (MYC), and alpha‑smooth muscle actin (ACTA2) had higher degrees. The hub genes of JUN, FOS, MYC and ACTA2, as well as the DEGs IL18 and CD274 that were associated with the immune response in GO terms may exert important functions in the molecular mechanisms of PABC. These genes may be used as new molecular targets in the treatment of this disease.
Related: Breast Cancer

Tran LS, Chonwerawong M, Ferrero RL
Regulation and functions of inflammasome-mediated cytokines in Helicobacter pylori infection.
Microbes Infect. 2017 Sep - Oct; 19(9-10):449-458 [PubMed] Related Publications
Persistent stomach infection with Helicobacter pylori causes chronic mucosal inflammation (gastritis), which is widely recognized as an essential precursor to gastric cancer. The IL-1 interleukin family cytokines IL-1β and IL-18 have emerged as central mediators of mucosal inflammation. Here, we review the regulation and functions of these cytokines in H. pylori-induced inflammation and carcinogenesis.
Related: Cytokines Stomach Cancer Gastric Cancer

Karan D, Tawfik O, Dubey S
Expression analysis of inflammasome sensors and implication of NLRP12 inflammasome in prostate cancer.
Sci Rep. 2017; 7(1):4378 [PubMed] Free Access to Full Article Related Publications
Inflammasomes are multi-proteins complex regulating inflammation-associated signaling. While inflammation plays a critical role in cancer cell growth, studies remain uncharacterized on the role of inflammasomes in prostate cancer. Using Gene Expression Omnibus (GEO) public datasets, we screened the expression profiles of inflammasome sensors NLRP3, NLRC4, NLRP6, NRLP12, and AIM2 in prostate tumor tissues, and verified their mRNA level in a panel of prostate cancer cell lines. The selected expression of NLRP3 and NLRP12 inflammasomes was validated, and the clinical association was evaluated in human prostate archival tumor tissues. We observed that the expression of inflammasome sensors was dysregulated at the mRNA level except for the NLRP12. The intensity of NLRP12 immunostaining was significantly higher in malignant prostate as compared to their adjacent benign tissues. In contrast, the NLRP3 immunostaining in prostate tissues was heterogeneous. The inflammasome complex proteins ASC (apoptosis-associated speck-like protein containing a CARD) and pro-caspase-1, as well as its downstream targets IL-1β and IL-18 were confined to aggressive prostate cancer cells. These data suggest an increased expression of NLRP12 in association with prostate cancer and support the role of NLRP12 inflammasome complex regulating inflammatory cytokines in understanding the role of inflammation in the prostate cancer.
Related: Prostate Cancer

Karki R, Malireddi RKS, Zhu Q, Kanneganti TD
NLRC3 regulates cellular proliferation and apoptosis to attenuate the development of colorectal cancer.
Cell Cycle. 2017; 16(13):1243-1251 [PubMed] Free Access to Full Article Related Publications
Nucleotide-binding domain, leucine-rich-repeat-containing proteins (NLRs) are intracellular innate immune sensors of pathogen-associated and damage-associated molecular patterns. NLRs regulate diverse biologic processes such as inflammatory responses, cell proliferation and death, and gut microbiota to attenuate tumorigenesis. In a recent publication in Nature, we identified NLRC3 as a negative regulator of PI3K-mTOR signaling and characterized its potential tumor suppressor function. Enterocytes lacking NLRC3 cannot control cellular proliferation because they are unable to suppress activation of PI3K-mTOR signaling pathways. In this Extra-View, we explore possible mechanisms through which NLRC3 regulates cellular proliferation and cell death. Besides interacting with PI3K, NLRC3 associates with TRAF6 and mTOR, confirming our recent finding that NLRC3 negatively regulates the PI3K-mTOR axis. Herein, we show that NLRC3 suppresses c-Myc expression and activation of PI3K-AKT targets FoxO3a and FoxO1 in the colon of Nlrc3
Related: Apoptosis Colorectal (Bowel) Cancer Signal Transduction

Baldini C, Santini E, Rossi C, et al.
The P2X7 receptor-NLRP3 inflammasome complex predicts the development of non-Hodgkin's lymphoma in Sjogren's syndrome: a prospective, observational, single-centre study.
J Intern Med. 2017; 282(2):175-186 [PubMed] Related Publications
BACKGROUND: P2X7 receptor (P2X7R), trigger of acute inflammatory responses via the NLRP3 inflammasome, is hyperfunctioning in patients with Sjögren's syndrome (SS), where it stimulates IL-18 production. Some patients with SS develop a mucosa-associated lymphoid tissue non-Hodgkin's lymphoma (MALT-NHL).
OBJECTIVES: To prospectively evaluate the involvement and the putative prognostic role of this inflammatory pathway in the development of MALT-NHL.
METHODS: A total of 147 women with SS have been prospectively followed for a mean of 52 months, relating the expression and function of the P2X7R-inflammasome axis in salivary glands and circulating lymphomonocytes to the prognosis and the degree of the disease.
RESULTS: At baseline, gene expression of P2X7R and of the inflammasome components NLRP3, caspase-1 and IL-18 increased according to the presence of germinative centres and was higher in autoantibody-positive individuals and strongly higher in those developing a MALT-NHL over the follow-up. Glandular expression of IL-18 was threefold higher in MALT-NHL than in controls or in the other patients with SS. P2X7R did not colocalize with generic markers of inflammatory infiltrate, like CD20, being selectively expressed by epithelial cells. P2X4R, sharing functional characteristics with P2X7R, did not differ in SS and controls. The increased P2X7R gene and protein expression was tissue specific, no difference being observed in peripheral lymphomonocytes between SS with MALT-NHL and SS not developing MALT-NHL.
CONCLUSION: We propose the P2X7R-inflammasome axis as a novel potential pathway involved in both SS exocrinopathy and lymphomagenesis, reinforcing the hypothesis of a key role of IL-18, via its increased P2X7R-mediated production, in the pathogenesis of lymphoproliferative malignancies, and opening novel opportunities for the early diagnosis of lymphoproliferative complications and the development of potential targeted therapies.
Related: MALT Lymphoma

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