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. Author manuscript; available in PMC: 2009 Jul 9.
Published in final edited form as: Cancer Cell. 2008 Aug 12;14(2):156–165. doi: 10.1016/j.ccr.2008.06.016

Figure 7. Control of ROS accumulation, IL-1α release, hepatocyte death, compensatory proliferation and their role in DEN-induced hepatocarcinogenesis.

Figure 7

IKKβ and p38α use different mechanisms to prevent ROS accumulation and excessive JNK activation and thereby maintain hepatocyte survival and suppress liver injury. Whereas IKKβ acts via NF-κB which induces expression of the antioxidants SOD2 and FHC, p38α upregulates expression of Hsp25, which also prevents ROS accumulation and subsequent Chop induction. Another consequence of ROS accumulation is inhibition of MKPs, resulting in prolonged JNK activation, which contributes to ROS accumulation and hepatocyte death. p38α is also involved in the negative regulation of IRF1 expression and a yet-to-be identified MKK4/7 kinase (MAP3K or MKKK). Increased MKK4/7 activity contributes to elevated JNK activity which promotes ROS accumulation. All of these pathways control hepatocyte death, which results in the release of IL-1α and activation of IL-1R/MyD88 signaling in Kupffer cells (KC), leading to activation of IKKβ and p38α, induction of IL-6 production, stimulation of compensatory proliferation and hepatocarcinogenesis.