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Verfasst von:Pinna, Federico [VerfasserIn]   i
 Bissinger, Michaela [VerfasserIn]   i
 Beuke, Katharina [VerfasserIn]   i
 Huber, Nicolas Peter [VerfasserIn]   i
 Kummer, Ursula [VerfasserIn]   i
 Schirmacher, Peter [VerfasserIn]   i
 Sahle, Sven [VerfasserIn]   i
 Breuhahn, Kai [VerfasserIn]   i
Titel:A20/TNFAIP3 discriminates tumor necrosis factor (TNF)-induced NF-[kappa]B from JNK pathway activation in hepatocytes
Verf.angabe:Federico Pinna, Michaela Bissinger, Katharina Beuke, Nicolas Huber, Thomas Longerich, Ursula Kummer, Peter Schirmacher, Sven Sahle, and Kai Breuhahn
E-Jahr:2017
Jahr:23 August 2017
Umfang:13 S.
Teil:volume:8
 year:2017
 elocationid:610
 extent:13
Fussnoten:Gesehen am 11.10.2018
Titel Quelle:Enthalten in: Frontiers in physiology
Ort Quelle:Lausanne : Frontiers Research Foundation, 2007
Jahr Quelle:2017
Band/Heft Quelle:8(2017), Artikel-ID 610
ISSN Quelle:1664-042X
Abstract:In the liver tumor necrosis factor (TNF)-induced signaling critically regulates the immune response of non-parenchymal cells as well as proliferation and apoptosis of hepatocytes via activation of the NF-κB and JNK pathways. Especially, the induction of negative feedback regulators such as IκBα and A20 is responsible for the dynamic and time-restricted response of these important pathways. However, the precise mechanisms responsible for different TNF-induced phenotypes under physiological stimulation conditions are not completely understood so far. In addition, it is not known if varying TNF concentrations may differentially affect the desensitization properties of both pathways. By using computational modeling, we first showed that TNF-induced activation and downstream signaling is qualitatively comparable between primary mouse hepatocytes and immortalized hepatocellular carcinoma (HCC) cells. In order to define physiologically relevant TNF levels, which allow for an adjustable and dynamic NF-κB/JNK pathway response in parenchymal liver cells, a range of cytokine concentrations was defined that led to gradual pathway responses in HCC cells (1-5 ng/ml). Repeated stimulations with low (1 ng/ml), medium (2.5 ng/ml) and high (5 ng/ml) TNF amounts demonstrated that JNK signaling was still active at cytokine concentrations, which led to dampened NF-κB signaling illustrating differential pathway responsiveness depending on TNF input dynamics. SiRNA-mediated inhibition of the negative feedback regulator A20 (syn. TNFAIP3) or its overexpression did not significantly affect the NF-κB response. In contrast, A20 silencing increased the JNK response, while its overexpression dampened JNK phosphorylation. In addition, the A20 knockdown sensitized hepatocellular cells to TNF-induced cleavage and activity of the effector caspase-3. In conclusion, a mathematical model-based approach shows that the TNF-induced pathway responses are qualitatively comparable in primary and immortalized mouse hepatocytes. The cytokine amount defines the pathway responsiveness under repeated treatment conditions with NF-κB signaling being dampened 'earlier' than JNK. A20 appears to be the molecular switch discriminating between NF-κB and JNK signaling when stimulating with varying physiological cytokine concentrations.
DOI:doi:10.3389/fphys.2017.00610
URL:Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.

Volltext ; Verlag: http://dx.doi.org/10.3389/fphys.2017.00610
 Volltext: https://www.frontiersin.org/articles/10.3389/fphys.2017.00610/full
 DOI: https://doi.org/10.3389/fphys.2017.00610
Datenträger:Online-Ressource
Sprache:eng
Sach-SW:Apoptosis
 computational modeling
 decision-making process
 Hepatocellular Carcinoma
 hepatocyte
K10plus-PPN:1581760590
Verknüpfungen:→ Zeitschrift

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