IFI16, an Interferon (IFN)-inducible gene in humans, is a member of the 200-amino acid repeat family of genes HIN200. We previously reported that enforced IFI16 expression in the first 48 h suppressed cell proliferation and resulted in upregulation of inflammatory molecules in human endothelial cells (EC). However, the fate of IFI16-overexpressing EC after inhibition of cell growth has not been clarified so far. Here, we show that IFI16 was sufficient to induce apoptosis, as measured by sub-G1 accumulation, Annexin V binding, and TUNEL analysis in the next 72 h after its overexpression. Activation of caspase 2 and caspase 3 was required for the full apoptotic effect, whereas their inactivation either by specific siRNAs or caspase-2 inhibitor abrogate cell death. IFI16 knockdown by specific siRNA partially prevented EC apoptosis triggered by IFN-beta priming followed by poly rI:rC treatment, proving its physiological relevance in IFN-mediated cell death. Finally, expression of a dominantnegative mutant of IKK2 kinase or treatment with AS602868, an inhibitor of IKK2 activity, halting IkB a degradation and NF-kB activation, resulted in lack of caspase 2 activation and apoptosis induction. We concluded that the IFN-inducible gene IFI16 may contribute to IFN-mediated inhibition of EC cell growth and tube morphogenesis by triggering caspase 2- and caspase 3-mediated programmed cell death through the NF-kB pathway

The interferon-inducible gene IFI16, a member of the HIN200 family, triggers primary endothelial cell apoptosis through caspase 2 and caspase 3 pathway

GUGLIESI, Francesca;DE ANDREA, Marco;CAPPELLO, Paola;GIOVARELLI, Mirella;LANDOLFO, Santo Giuseppe
2009

Abstract

IFI16, an Interferon (IFN)-inducible gene in humans, is a member of the 200-amino acid repeat family of genes HIN200. We previously reported that enforced IFI16 expression in the first 48 h suppressed cell proliferation and resulted in upregulation of inflammatory molecules in human endothelial cells (EC). However, the fate of IFI16-overexpressing EC after inhibition of cell growth has not been clarified so far. Here, we show that IFI16 was sufficient to induce apoptosis, as measured by sub-G1 accumulation, Annexin V binding, and TUNEL analysis in the next 72 h after its overexpression. Activation of caspase 2 and caspase 3 was required for the full apoptotic effect, whereas their inactivation either by specific siRNAs or caspase-2 inhibitor abrogate cell death. IFI16 knockdown by specific siRNA partially prevented EC apoptosis triggered by IFN-beta priming followed by poly rI:rC treatment, proving its physiological relevance in IFN-mediated cell death. Finally, expression of a dominantnegative mutant of IKK2 kinase or treatment with AS602868, an inhibitor of IKK2 activity, halting IkB a degradation and NF-kB activation, resulted in lack of caspase 2 activation and apoptosis induction. We concluded that the IFN-inducible gene IFI16 may contribute to IFN-mediated inhibition of EC cell growth and tube morphogenesis by triggering caspase 2- and caspase 3-mediated programmed cell death through the NF-kB pathway
Tri-Society Annual Conference 2009 of the Society for Leukocyte Biology, International Cytokine Society, & International Society for Interferon and Cytokine Research, Cellular and Cytokine Interactions in Health and Disease
Lisbon, Portugal
October 18-21, 2009
48
85
85
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WDF-4X8C4P6-BK&_user=525216&_coverDate=11%2F30%2F2009&_rdoc=1&_fmt=high&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000026382&_version=1&_urlVersion=0&_userid=525216&md5=af0e4b8324f79a19b55d6e4cddef5517
IFI16; apoptosis; endotelial cells
Gugliesi F; De Andrea M; Mondini M; Cappello P; Giovarelli M; Gariglio M; Landolfo S
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/146630
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