The IL-18 antagonist IL-18 Binding Protein is produced in the human ovarian cancer microenvironment
Menée in vitro, in vivo et sur des échantillons tumoraux, cette étude met en évidence des mécanismes par lesquels la protéine se liant à l'interleukine 18, produite dans des cellules épithéliales de l'ovaire en réponse à des facteurs du micro-environnement, est susceptible d'inhiber l'activité de l'interleukine 18
Purpose:Interleukin (IL)-18 is an immune-enhancing cytokine, which induces Interferon (IFN)-γ production, Th1-responses and anti-tumor effects. In turn, IFN-γ stimulates IL-18 Binding Protein (BP) production, which blocks IL-18 activity. In view of the potential use of IL-18 in epithelial ovarian cancer (EOC) immunotherapy, here we studied IL-18BP expression and its regulation by cytokines in EOC cells in vitro and in vivo. Experimental Design:Expression and production of IL-18BP in EOC cell lines, primary ovarian carcinomas and the corresponding normal tissues, patients' serum and ascites were investigated by immunochemistry, ELISA, screening of gene expression profiles and RT-PCR. Results:Analysis of gene expression profiles revealed that IL18BP mRNA is increased in EOC tumors compared to normal ovary cells. Release of IL-18BP was detectable in EOC sera and at greater extent in the ascites, indicating production at the tumor site. Indeed, immunochemical analyses on cells isolated from the ascites and on tumor sections indicated that IL-18BP is expressed in both tumor cells and tumor-associated leukocytes, which displayed a CD3-CD20-NKp46-CD13+CD14low phenotype. EOC cell lines do not constitutively express IL-18BP. However, its release is inducible both by IFN-γ stimulation in vitro and by xenotransplantation of EOC cells in immune-deficient mice, suggesting a role for the microenvironment. In vitro experiments and immunochemistry indicated that also IL-27 is involved in IL-18BP up-regulation in EOC cell lines and primary cells through STAT1 activation. Conclusions:Altogether these data indicate that IL-18BP, which is produced in EOC in response to micro-environmental factors, may inhibit endogenous or exogenous IL-18 activity.