Elsevier

Human Immunology

Volume 71, Issue 3, March 2010, Pages 309-313
Human Immunology

Impact of interleukin-18 polymorphisms-607 and -137 on clinical characteristics of renal cell carcinoma patients

https://doi.org/10.1016/j.humimm.2009.11.010Get rights and content

Abstract

Current evidence suggests that chronic inflammation is associated with tumor development and progression. Interleukin-18 (IL-18) plays a central role in inflammation and the immune response, contributing to the pathogenesis and pathophysiology of infectious and inflammatory diseases. The objective of this study was to determine whether the presence of IL-18 polymorphisms -137 G/C (rs187238) and -607 A/C (rs1946518) was associated with size, grade, TNM stage, and survival in patients with renal cell carcinoma (RCC). The study cohort included 158 patients with RCC. Control group consisted of 506 samples from Spanish population. The studied IL-18 gene polymorphisms did not influence susceptibility to RCC in the analyzed group of patients (IL-18-607, p = 0.318; IL-18-137 p = 0.740) but may contribute to disease onset and aggressiveness. IL-18-607 CC genotype was significantly associated with higher tumor size (p = 0.001), grade (p = 0.030), T (p = 0.001), M (p = 0.012), and stage (p = 0.002). IL-18-103 GG genotype was correlated with higher tumor size (p = 0.036), grade (p = 0.017), T (p = 0.026), and stage (p = 0.011). The Cox proportional hazard model showed that nuclear grade and stage grouping were independent prognostic factors but IL-18 polymorphism was not. Polymorphism variants in the IL-18 gene (IL-18-607 and IL-18-137) may be associated with a worse prognosis for RCC. High levels of IL-18 production may play a major role in the growth, invasion and metastasis of renal cancer.

Introduction

Renal cell carcinoma (RCC) is the most common renal tumor and represents 2%–3% of all malignancies. RCC is two fold more frequent in men than in women, and the highest RCC incidence is observed in the sixth decade [1]. Considerable evidence has been published over the past few years linking increased tumor risk with inflammation, and clinical and experimental studies have associated tumor progression with the upregulation of proinflammatory molecules, especially during late stages of the disease [2], [3]. Chronic inflammation, alongside the intrinsic properties of premalignant cells and other determinants, may be one of the driving forces of tumor initiation and promotion. Thus, numerous mediators released in dysregulated chronic inflammation were found to promote cell growth and invasion, inducing mutagenesis and increasing angiogenicity [4]. In this context, genetic polymorphisms in different inflammatory cytokine have been associated with cancer risk and the growth or invasiveness of RCC and others types of tumor [5], [6], [7].

Interleukin (IL)-18 was discovered as an interferon (IFN)-γ–inducing factor. IL-18 is a member of the IL-1 family, and its receptor belongs to the IL-1 receptor family. When IL-18 binds to IL-18Rα, IL-18Rβ transduces its signal to stimulate the mitogen-activated protein kinase pathway, which is involved in producing IFN-γ [8]. IL-18 can activate immune cells, with or without IL-12 [9], promoting the activation and proliferation of T and natural killer cells [10], [11]. Transformed cells and tumors are effectively eliminated by IL-18-mediated activation of immune cells such as cytotoxic T cells and natural killer cells [12]. Intratumoral injection of IL-18 DNA enhances IFN-γ production, causes regression of liver tumor and has been proposed as a cancer treatment [13]. B7-1 costimulatory molecule in combination with IL-18 was used by Cho et al. against malignant skin tumors, including melanoma [14].

However, IL-18 can also promote tumor cells, as evidenced by the elevated expression of IL-18 in tumor cells [15], [16]. IL-18 expression was also elevated in the tumor versus nontumor area in gastric cancer patients and was related to distant metastasis [17]. Higher IL-18 levels were found in serum from breast cancer patients with than without metastasis and were proposed as an important marker of breast cancer progression [18]. It also enhances immune escape by promoting the expression of Fas ligand in tumor cells and downregulating major histocompatibility complex class I expression [19], [20].

We have described previously that the proangiogenic function of other interleukins (e.g., IL-10) [6] could have an important role in RCC growth and metastasis. IL-18 plays a major role in angiogenesis. The induction of IL-18 by hypoxia or inflammatory cells augments the expression of hypoxia-inducible factor (HIF)-1α and tumor cell metastases [21]. IL-18 proangiogenic functions are essential for tumor growth [22].

Hence, IL-18 can stimulate the immune system against tumor cells but can also induce angiogenesis, metastasis, proliferation, and immune escape [23]. The objective of this study was to determine the role in RCC of two single-nucleotide polymorphisms (SNPs) in the IL-18 promoter region, which are known to alter IL-18 promoter activity. Allele C at -607 position and allele G at -137 position (-607 A/C [rs1946518] and -137 G/C [rs187238], respectively) are correlated with higher serum levels of IL-18 [24].

Section snippets

Patients

The study included 158 patients diagnosed with clear-cell renal carcinoma (RCC) at the Department of Urology of Virgen de las Nieves Hospital between 1997 and 2008. All patients had undergone radical or partial nephrectomy. The mean age was 60 years (range, 23–84 years). Clinicopathological characteristics are shown in Table 1. Two consulting pathologists retrospectively and independently reviewed the hematoxylin and eosinstained tissue slides according to the World Health Association

IL-18 genotypes and cancer risk

This case-control study revealed similar frequencies in the distribution of IL-18-137 and -607 polymorphisms between healthy controls and patients with RCC (p = 0.1 and p = 0.3, respectively, for allele frequencies). Table 2 presents the genotype distributions and statistical analysis. The observed genotype frequencies were in accordance with Hardy–Weinberg equilibrium. The allele distribution and haplotypes of the control group were previously published [26] and were similar to other reports

Discussion

The etiology of renal cancer is highly complex and involves both environmental and genetic factors. Chronic inflammation appears to make an essential contribution [28]. In addition, genetic polymorphisms in cytokine genes can influence the expression or function of these cytokines, and polymorphisms in genes that regulate the intensity of immune responses may contribute to the pathogenesis of renal cancer and influence the clinical outcome of patients [6], [29]. This study analyzed genetic

Acknowledgments

We thank Ms. Eva García and Ms. Ana Isabel Rodríguez for technical assistance. This study was supported by grants from the Fondo de Investigaciones Sanitarias (FIS), Red Genomica del Cancer (RETIC RD 06/0020), Plan Andaluz de Investigacion (Group CTS 143), Consejeria Andaluz de Salud (SAS), Proyecto de Excelencia de Consejeria de Innovacion (CTS 695), Proyecto de investigacion I+D (SAF 2007-63262) in Spain; and from the Integrated European Cancer Immunotherapy project (OJ2004/C158, 518234).

References (42)

  • K. Nakanishi et al.

    Interleukin-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu

    Cytokine Growth Factor Rev

    (2001)
  • M.L. Cho et al.

    Interleukin-18 induces the production of vascular endothelial growth factor (VEGF) in rheumatoid arthritis synovial fibroblasts via AP-1-dependent pathways

    Immunol Lett

    (2006)
  • M.K. Jung et al.

    IL-18 enhances the migration ability of murine melanoma cells through the generation of ROI and the MAPK pathway

    Immunol Lett

    (2006)
  • F. Balkwill

    Chemokine biology in cancer

    Semin Immunol

    (2003)
  • A.L. Kung et al.

    Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway

    Cancer Cell

    (2004)
  • P. Mulders et al.

    Renal cell carcinoma: Recent progress and future directions

    Cancer Res

    (1997)
  • D. Nelson et al.

    Tumor growth or regression: Powered by inflammation

    J Leukoc Biol

    (2006)
  • L.M. Coussens et al.

    Inflammation and cancer

    Nature

    (2002)
  • P. Sáenz-López et al.

    Polymorphisms of RANTES, IL1-A, MCP-1 and TNF-A genes in patients with prostate cancer

    BMC Cancer

    (2008)
  • H. Okamura et al.

    Cloning of a new cytokine that induces IFN-γ production by T cells

    Nature

    (1995)
  • K. Barbulescu et al.

    IL-12 and IL-18 differentially regulate the transcriptional activity of the human IFN-γ promoter in primary CD4+ T lymphocytes

    J Immunol

    (1998)
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    The authors Pablo Sáenz-López and Rafael Carretero have equally contributed to this work and the two should be considered as first authors.

    The José Manuel Cózar and Francisco Ruiz-Cabello authors have equally contributed to this work and the two should be considered as last authors.

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