کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
3299543 1209932 2007 15 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Genetic Inactivation of RelA/p65 Sensitizes Adult Mouse Hepatocytes to TNF-induced Apoptosis In Vivo and In Vitro
موضوعات مرتبط
علوم پزشکی و سلامت پزشکی و دندانپزشکی بیماری‌های گوارشی
پیش نمایش صفحه اول مقاله
Genetic Inactivation of RelA/p65 Sensitizes Adult Mouse Hepatocytes to TNF-induced Apoptosis In Vivo and In Vitro
چکیده انگلیسی

Background & Aims: The transcription factor nuclear factor (NF)-κB plays a critical role in mediating survival of hepatocytes in response to tumor necrosis factor (TNF)-α during development because mice deficient for the NF-κB subunit RelA/p65 die in utero because of TNF-induced liver apoptosis. For the adult liver, conflicting concepts exist as to whether soluble TNF can trigger apoptosis when NF-κB activation is impaired. By creating a mouse model in which the transactivating NF-κB subunit RelA/p65 can be genetically inactivated in hepatocytes using the Cre/lox system, we sought to clarify the role of NF-κB in TNF-mediated hepatocyte apoptosis. Methods: Deletion of RelA/p65 in the liver was achieved using an inducible conditional knockout system (relaF/FMxCre mice) or, hepatocyte-specifically, using a developmental conditional knockout system (relaF/FAlbCre mice). Results: Disruption of RelA/p65 rendered mice sensitive to lethal liver injury upon TNF administration. Primary RelA/p65-deficient hepatocytes showed no NF-κB activation and undergo rapid apoptosis after TNF treatment. In contrast, hepatocytes deficient for IκB-kinase β (IKKβ), displayed residual NF-κB activity and consecutively only mild apoptosis in response to TNF. TNF-induced apoptosis in RelA/p65-deficient hepatocytes was accompanied by prolonged activation of c-jun activating kinase (JNK) and rapid, largely proteasome-independent elimination of the long splice form of the antiapoptotic cellular FLICE inhibitor protein (c-FLIPL). Gene silencing of caspase-8, caspase-inhibitors, inhibition of JNK, or administration of antioxidants inhibited apoptosis and elimination of c-FLIPL. Conclusions: RelA/p65 is essential for TNF-induced NF-κB activation in adult hepatocytes. Genetic deletion of a functional RelA/p65 sensitizes these cells to apoptosis in response to soluble TNF in vivo and in vitro.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Gastroenterology - Volume 132, Issue 7, June 2007, Pages 2489–2503
نویسندگان
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