The proapoptotic activity of the Interferon-inducible gene IFI16 provides new insights into its etiopathogenetic role in autoimmunity.
Several lines of evidence link Interferons (IFNs) with autoimmune disorders. Autoantibodies against the Interferon-inducible IFI16 protein, a member of the HIN-200 family constitutively expressed in endothelial cells and keratinocytes, have been identified in patients affected by autoimmune diseases including Systemic Lupus Erythematosus (SLE), Sjogren Syndrome (SjS), and Scleroderma (SSc). These findings point to a role for IFI16 in the etiopathogenesis of autoimmune diseases, but the exact mechanisms involved in the development of autoimmunity remain obscure. In this study, we report for the first time that endothelial cells overexpressing IFI16 undergo apoptosis via the activation of caspase 2 and caspase 3, and that a positive feedback loop appears to link these two caspases. The relevance of IFI16-mediated apoptosis is highlighted by the observation that IFI16 knock down by RNA interference in endothelial cells inhibits the activation of both caspase 2 and caspase 3 by IFN-beta priming and synthetic double-stranded RNA treatment. Expression of a dominant-negative mutant of IKK2 kinase or treatment with AS602868, an inhibitor of IKK2 activity, results in a strong reduction of NF-kB activation along with absence of caspase 2 and caspase 3 activation and apoptosis induction. Collectively, our findings provide new insights into the role of IFI16 in the pathogenesis of autoimmune diseases by demonstrating that in addition to the stimulation of pro-inflammatory molecules, IFI16 also leads to apoptosis in endothelial cells.
Gugliesi
Francesca
F
Department of Public Health and Microbiology, University of Turin, Via Santena 9, Turin, Italy.
De Andrea
Marco
M
Mondini
Michele
M
Cappello
Paola
P
Giovarelli
Mirella
M
Shoenfeld
Yehuda
Y
Meroni
PierLuigi
P
Gariglio
Marisa
M
Landolfo
Santo
S
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity; D053143:Caspase 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000276:immunology / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D019076:Transgenes / Q000235:genetics
C519899:AS602868; D016328:NF-kappa B; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011743:Pyrimidines; D012330:RNA, Double-Stranded; D034741:RNA, Small Interfering; C076700:IFI16 protein, human; D016899:Interferon-beta; D051550:I-kappa B Kinase; D053143:Caspase 2; D053148:Caspase 3