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A novel isoform of pro-interleukin-18 expressed in ovarian tumors is resistant to caspase-1 and -4 processing

Oncogene volume 23, pages 7552–7560 (2004)Cite this article

Abstract

Interleukin-18 (IL-18) is a proinflammatory cytokine synthesized as a 24 kDa inactive precursor (pro-IL-18) by several cell types, and is processed to a bioactive molecule of 18 kDa by the proteinases caspase-1 or caspase-4. All ovarian carcinoma cell lines express pro-IL-18, only in some instances coexpress caspase-1, and always express caspase-4; in any case, they display a defective processing of IL-18. We analysed whether pro-IL-18, present in two ovarian carcinoma cell lysates, could be processed ‘in vitro’ by recombinant active caspase-1. While most of pro-IL-18 could be cleaved by caspase-1, a residual of pro-IL-18 appeared to be resistant. Cloning and sequence analysis of the whole pro-IL-18 open reading frame demonstrated the existence of an alternatively spliced mRNA variant, which lacked exon-3 (Δ3pro-IL-18). The 12 bp exon-3 encodes for the AEDD amino-acid sequence, which is N-terminal with respect to the cleavage site of caspase-1. Both pro-IL-18 and Δ3pro-IL-18 mRNA isoforms were detected in all ovarian cancer cell lines analysed, while Δ3pro-IL-18 mRNA was undetectable in normal ovarian epithelial cells. The Δ3pro-IL-18 cDNA induced synthesis of an alternative Δ3pro-IL-18 protein upon transfection into a murine cell line. The Δ3pro-IL-18 protein was resistant to proteolytic activation by caspase-1 and -4, although it was capable to bind caspase-1. Aternative splicing of pro-IL-18 exon-3 may represent a novel mechanism of regulation of bioactive IL-18 production in human ovarian tumors.

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Acknowledgements

This study was supported by grants awarded by AIRC (Italian Association for Cancer Research), Ministero della Salute, CARIPLO Foundation and MIUR.

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Authors and Affiliations

  1. Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi 10, Genoa, 16132, Italy

    Alessia Gaggero, Alessandro De Ambrosis, Tiziana Piazza, Anna Rubartelli & Silvano Ferrini

  2. Istituto Nazionale Tumori, Via G Venezian 1, Milan, 20133, Italy

    Delia Mezzanzanica, Mariangela Figini & Silvana Canevari

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  1. Alessia Gaggero
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  2. Alessandro De Ambrosis
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Correspondence to Silvano Ferrini.

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Gaggero, A., Ambrosis, A., Mezzanzanica, D. et al. A novel isoform of pro-interleukin-18 expressed in ovarian tumors is resistant to caspase-1 and -4 processing. Oncogene 23, 7552–7560 (2004). https://doi.org/10.1038/sj.onc.1208036

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