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Koppe, C.* ; Reisinger, F. ; Wehr, K.* ; Vucur, M.* ; Trautwein, C.* ; Tacke, F.* ; Heikenwalder, M.* ; Luedde, T.*

An NF-kappaB- and IKK-independent function of NEMO prevents hepatocarcinogenesis by suppressing compensatory liver regeneration.

Cancers 11:999 (2019)

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The I-kappa B-Kinase (IKK) complex represents a central signaling nexus in the TNF-dependent activation of the pro-inflammatory NF-kappa B pathway. However, recent studies suggested that the distinct IKK subunits (IKK alpha, IKK beta, and NEMO) might withhold additional NF-kappa B-independent functions in inflammation and cancer. Here, we generated mice lacking all three IKK subunits in liver parenchymal cells (LPC) (IKK alpha/beta/NEMOLPC-KO) and compared their phenotype with mice lacking both catalytic subunits (IKK alpha/beta(LPC-KO)), allowing to functionally dissect putative I-kappa B-Kinase-independent functions of the regulatory subunit NEMO. We show that the additional deletion of NEMO rescues IKK alpha/beta(LPC-KO) mice from lethal cholestasis and biliary ductopenia by triggering LPC apoptosis and inducing a strong compensatory proliferation of LPC including cholangiocytes. Beyond this beneficial effect, we show that increased hepatocyte cell-death and compensatory proliferation inhibit the activation of LPC-necroptosis but trigger spontaneous hepatocarcinogenesis in IKK alpha/beta/NEMOLPC-KO mice. Collectively, our data show that free NEMO molecules unbound to the catalytic IKK subunits control LPC programmed cell death pathways and proliferation, cholestasis and hepatocarcinogenesis independently of an IKK-related function. These findings support the idea of different functional levels at which NEMO controls inflammation and cancer in the liver.

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