title: The IL-18 antagonist IL-18-binding protein is produced in the human ovarian cancer microenvironment.
abstract: OBJECTIVE
  Interleukin (IL)-18 is an immune-enhancing cytokine, which induces IFN-γ production, T-helper 1 responses, and antitumor effects. In turn, IFN-γ stimulates IL-18-binding protein 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.
  
  
  METHODS
  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 reverse-transcription PCR.
  
  
  RESULTS
  Analysis of gene expression profiles revealed that IL18BP mRNA is increased in EOC tumors compared with normal ovary cells. Release of IL-18BP was detectable in EOC sera and to a 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 IL-27 is also involved in IL-18BP upregulation in EOC cell lines and primary cells through STAT1 activation. Together, these data indicate that IL-18BP, which is produced in EOC in response to microenvironmental factors, may inhibit endogenous or exogenous IL-18 activity.
authors.affiliation: Department of Integrated Oncological Therapies, IRCCS AOU San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Carbotti
authors.forename: Gaia
authors.initials: G
authors.lastname: Barisione
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Orengo
authors.forename: Antonella
authors.initials: A
authors.lastname: Brizzolara
authors.forename: Irma
authors.initials: I
authors.lastname: Airoldi
authors.forename: Marina
authors.initials: M
authors.lastname: Bagnoli
authors.forename: Patrizia
authors.initials: P
authors.lastname: Pinciroli
authors.forename: Delia
authors.initials: D
authors.lastname: Mezzanzanica
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Centurioni
authors.forename: Marina
authors.initials: M
authors.lastname: Fabbi
authors.forename: Silvano
authors.initials: S
authors.lastname: Ferrini
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007167:Immunotherapy; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000097:blood / Q000235:genetics*; D007371:Interferon-gamma / Q000235:genetics; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000097:blood* / Q000235:genetics* / Q000473:pathology; D050794:STAT1 Transcription Factor / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D007378:Interleukins; C464565:MYDGF protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C118370:interleukin-18 binding protein; D007371:Interferon-gamma