Cancer Letters

Cancer Letters

Volume 142, Issue 2, 3 August 1999, Pages 179-184
Cancer Letters

Interleukin-1 receptor antagonist mRNA expression and the progression of gastric carcinoma

https://doi.org/10.1016/S0304-3835(99)00162-7Get rights and content

Abstract

Interleukin-1 receptor antagonist (IL-1ra), an endogeneous inhibitor of IL-1, plays an immunosuppressive role in vivo by blocking the proinflammatory effects of IL-1. In the present study, we examined whether IL-1ra expression in human gastric carcinoma correlates with tumor progression and/or metastatic potential. The reverse transcription-polymerase chain reaction was used to compare the expression of the secreted form of IL-1ra (sIL-1ra) and the intracellular form of IL-1ra (icIL-1ra) mRNA in tumor and corresponding benign tissue obtained from 38 patients with gastric carcinoma. The incidence of sIL-1ra mRNA expression was significantly higher in tumor (52%) than in corresponding benign tissue (18%) (P=0.002). On the contrary, icIL-1ra mRNA was detected in all tumors and benign tissues. The expression of sIL-1ra mRNA by malignant tissue correlated positively with both lymph node metastasis (P=0.008) and liver metastasis (P=0.015). There was no association between tumor sIL-1ra mRNA expression and other clinicopathologic factors. The degree of regional lymph node reaction, such as sinus histiocytosis, in tumors expressing sIL-1ra mRNA was significantly weaker than that in tumors without sIL-1ra mRNA expression (5/20 vs. 12/18, P=0.010). These results demonstrate that the altered expression of sIL-1ra by malignant tissue may be related to the progression of gastric carcinoma via modulating host immune response.

Introduction

We have previously reported that the host immune response is a favorable prognostic factor in human gastric carcinoma [1]. It also has been reported that immunochemotherapy with protein-bound polysaccharide (PSK), a biological response modifier, has a beneficial effect when used following curative gastrectomy [2]. In addition to these clinical reports, using gastric carcinoma cells engineered to produce cytokines, Tagawa et al. demonstrated that its tumorigenicity was significantly reduced in severe combined immunodeficiency (SCID) mice [3]. These studies suggest that the progression of gastric carcinoma is closely related to the host immune reaction.

It is known that interleukin-1 (IL-1) upregulates the activity of T cells, natural killer (NK) cells and macrophages, which plays important roles in anti-tumor immunity [4], [5], [6], [7]. Recently, interleukin-1 receptor antagonist (IL-1ra) cDNA, an endogeneous IL-1 inhibitor, was isolated and sequenced from human monocytes [8], [9]. Furthermore, IL-1 blockade by administration of recombinant IL-1ra, was reported to downregulate the activity of IL-2-induced lymphokine-activated killer (LAK) cells [10]. Recent studies also showed that human lung carcinoma and glioblastoma also elaborated IL-1ra, however, the relationship between IL-1ra and tumor progression in these malignancies remains unclear [11], [12]. Taken together, we postulated that the presence of endogeneous IL-1ra in gastric carcinoma may be related to tumor progression and/or metastasis. However, the intracellular form of IL-1ra (icIL-1ra), an isoform of IL-1ra that exhibits high homology with the secreted form of IL-1ra (sIL-1ra), has been confirmed to be present in human epithelial cells [13]. Because of the high homology, it is difficult to analyze the both types of IL-1ra at protein level. Therefore, in the present study, we evaluated both sIL-1ra and icIL-1ra mRNA expression in human gastric carcinoma by reverse trascription-polymerase chain reaction (RT-PCR), which is capable of distinguishing sIL-1ra mRNA from icIL-1ra mRNA.

Section snippets

Patients

IL-1ra mRNA expression was analyzed in 38 patients who underwent surgical resection of gastric carcinoma at Yamaguchi University Hospital between June 1993 and May 1995. The patients included 31 men and seven women aged 37–78 years (mean, 64 years). A histopathologic diagnosis of gastric carcinoma was in accordance with the generally accepted criteria for this malignancy [14]. Tumors were divided into two histologic subgroups, intestinal type and diffuse type, according to Lauren's

Results

We detected sIL-1ra mRNA in 20 of 38 (52.6%) tumors and in only seven of 38 (18.4%) corresponding benign tissues. sIL-1ra mRNA was not detected in the remaining samples. Therefore, the frequency of sIL-1ra mRNA expression was significantly higher in malignant than in benign tissue (χ2=9.7082, P=0.002) (Table 1). On the contrary, icIL-1ra mRNA was detected in all tumors and benign tissues (Table 1). IL-1β mRNA expression also was detected in all tumors (data not shown). In order to determine the

Discussion

Smith et al. showed that tissue levels of IL-1ra protein were significantly higher in lung carcinoma than in normal lung, however, it is unclear if there is a relationship between IL-1ra expression and tumor progression [11]. Since we could not confirm sIL-1ra mRNA in all of the six esophageal cancer cell lines [18], it is possible that the major part of IL-1ra elaborated by lung carcinoma may be the intracellular form. Thus, it may be difficult to compare the expression of two isoforms of

Acknowledgements

This work was supported in part by a Grant-in-Aid from the Ministry of Education, Science and Culture of Japan.

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