Clinical significance of interleukin-1 receptor antagonist in patients with cervical carcinoma

doi:10.1016/S0090-8258(02)00154-3

Gynecologic Oncology

Volume 89, Issue 1, April 2003, Pages 77-83

https://doi.org/10.1016/S0090-8258(02)00154-3 Get rights and content

Abstract

Objective

Our purpose was to determine the clinical significance of interleukin-1 receptor antagonist (IL-1ra), which is an endogenous inhibitor cytokine of IL-1, in patients with cervical carcinoma.

Methods

Tissue IL-1ra expression and serum IL-1ra level were examined by enzyme-linked immunosorbent assay (ELISA), Western blotting, and immunohistochemistry in normal controls and patients with cervical carcinoma.

Results

Tissue IL-1ra protein level by ELISA was significantly higher in squamous cell carcinoma (n = 9) than in the normal cervix (n = 7) and adenocarcinoma (n = 3). Western blotting confirmed the main presence of intracellular IL-1ra type 1 in squamous cell carcinoma. Immunohistochemistry demonstrated significant IL-1ra expression only in tumor cells of squamous cell carcinoma. Elevation of serum IL-1ra level was found in patients with squamous cell carcinoma (n = 38) compared to normal women (n = 13), but not in patients with adenocarcinoma (n = 9). Although serum IL-1ra level did not correlate with clinical stage or any other tumor marker, high serum IL-1ra level was associated with pelvic lymph node metastasis and poor prognosis in patients with squamous cell carcinoma. On the other hand, these results were not obtained in patients with cervical adenocarcinoma.

Conclusion

IL-1ra may play important roles in local and general malignant behaviors in patients with cervical squamous cell carcinoma, and measurement of serum IL-1ra level may be useful in predicting patient survival.

Introduction

Interleukin-1 (IL-1), which indicates the two structurally related subtypes IL-1α and IL-1β, is a cytokine that shows a wide spectrum of inflammatory, metabolic, physiological, and immunological properties [1], [2], [3]. Recently, IL-1 receptor antagonist (IL-1ra), which is a naturally occurring antagonist for IL-1, has been characterized [1], [2], [3]. The encoded protein shows some amino acid homology with IL-1 α and IL-1 β binding to the IL-1 receptor without initiating IL-1 signal transduction, and can block a multitude of IL-1 effects. Expression of an endogenous IL-1ra is part of the complex regulation of IL-1. Three splice variant forms of the IL-1ra gene product, such as secretary IL-1ra (sIL-1ra) and two intracellular forms (icIL-1ra type 1 and icIL-1ra type II), have been described [3], [4]. Additionally, several molecular forms of sIL-1ra, which differ in the degree of glycosylation, have been reported. With regard to biological activity, sIL-1ra and icIL-1ra type I are known to bind to the IL-1 receptor type 1 with pure antagonistic activity. However, the functional significance of glycosylation of sIL-1ra and in vivo translation of icIL-1ra type II into functional protein remains unclear.

Expression and function of IL-1ra has widely been investigated in various human diseases [1], [2], [3]. The majority of these studies concerned inflammatory and immunologically mediated diseases, but IL-1ra has also been associated with human malignancies [5], [6], [7], [8], [9], [10]. Cervical carcinoma is one of the most common tumors in the world, and infection with specific types of human papillomavirus (HPV) is important in the pathogenesis of cervical carcinoma. The host’s cell-mediated immune response, which is partially controlled by an IL-1 dependent pathway, influences both susceptibility to and regression of HPV infections. Although in vitro studies showed that expression of several cytokines including IL-1ra varied in cultured normal cervical cells, cervical cells immortalized by HPV DNAs, and cervical carcinoma cells [10], in vivo IL-1ra expression in cervical carcinoma has not been reported. In experimental models, a large excess of IL-1ra (10²- to 10⁴-fold) is generally required to reduce by 50% or block the biological response to IL-1 [3]. IL-1 α and IL-1 β are not readily secreted from the cells into the systemic circulation, but IL-1ra is readily secreted from cells into circulation [1]. Our preliminary report showed significantly increased serum IL-1ra levels in patients with gynecologic cancers compared to those with benign gynecologic diseases or healthy women, without significant increases in serum IL-1 β level [5]. Therefore, circulating IL-1ra may be a more useful tumor marker than IL-1 itself for these patients and may play important roles in these malignant conditions. However, the clinical and prognostic significances of serum IL-1ra level for cancer patients have not been determined.

In this study, we examined tissue and serum IL-1ra levels by enzyme-linked immunosorbent assay (ELISA), protein expression by Western blotting, and protein localization by immunohistochemistry in cervical carcinomas and normal controls. The clinical significance of IL-1ra for patients with cervical carcinoma was investigated.

Section snippets

Patients

Patients for this study were selected from cases of cervical carcinoma treated at Shimane Medical University Hospital, Izumo, Japan, and Kumamoto University Hospital, Kumamoto, Japan, between January 1994 and December 1999. Informed consent was obtained from each patient before the collection of serum or tissue specimens. Forty-seven serum samples from patients with cervical carcinoma and 13 samples from healthy women as a control were used for determination of the serum IL-1ra level. The

IL-1ra expression in tissue specimens

Tissue IL-1ra protein level by ELISA was significantly higher in squamous cell carcinoma than in the normal cervix and adenocarcinoma (Table 1; both P < 0.05). There was no difference of tissue IL-1ra level between the normal cervix and adenocarcinoma.

To examine the expression of variant forms of IL-1ra, we determined IL-1ra protein expression by Western blot analysis (Fig. 1). Nearly all squamous cell carcinomas expressed icIL-1ra type I (18 kDa) at a strong level and glycosylated sIL-1ra (22

Discussion

In this study, we found that tissue IL-1ra protein level by ELISA was significantly elevated in cervical squamous cell carcinoma compared to the normal cervix. Western blot analysis confirmed the main presence of icIL-1ra type I, which is produced by keratinocytes and other epithelial organs [2], in cervical squamous cell carcinoma. Immunohistochemical analysis demonstrated diffuse IL-1ra expression throughout the tumor cell with no staining of the surrounding stromal cell, suggesting that

Acknowledgements

This work was supported in part by a Grant-in-Aid from Japan Society for the Promotion of Science (No. 13770917). We thank Mr. Mikio Koike, Laboratory Medicine and Central Clinical Laboratory, Shimane Medical University, for providing paraffin-embedded tissues, and Miss. Taeko Yamada, Department of Obstetrics and Gynecology, Shimane Medical University, for management of medical records.

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Regular articleClinical significance of interleukin-1 receptor antagonist in patients with cervical carcinoma

Abstract

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Patients

IL-1ra expression in tissue specimens

Discussion

Acknowledgements

Adv Immunol

Lancet

Gynecol Oncol

Blood

Am J Obstet Gynecol

Interleukin-1, interleukin-1 receptors and interleukin-1 receptor antagonist

Int Rev Immunol

Interleukin 1 receptor antagonist. A new member of the interleukin 1 family

J Clin Invest

Cloning and characterization of a new isoform of the interleukin 1 receptor antagonist

J Exp Med

Elevation of serum interleukin-1 receptor antagonist levels in women with gynaecological cancers

Br J Obstet Gynaecol

Regular article
Clinical significance of interleukin-1 receptor antagonist in patients with cervical carcinoma