Reg2 inactivation increases sensitivity to Fas hepatotoxicity and delays liver regeneration post-hepatectomy in mice.
Reg2/RegIIIbeta is the murine homologue of the human secreted HIP/ PAP C-type lectin. HIP/ PAP transgenic mice were protected against acetaminophen-induced acute liver failure and were stimulated to regenerate post-hepatectomy. To assess the role of Reg2, we used Reg2-/- mice in a model of fulminant hepatitis induced by Fas and in the post-hepatectomy regeneration. Within 4 hours of J0-2 treatment (0.5 mug/g), only 50% of the Reg2-/- mice were alive but with an increased sensitivity to Fas-induced oxidative stress and a decreased level of Bcl-xL. In contrast, HIP/ PAP transgenic mice were resistant to Fas, with HIP/ PAP serving as a sulfhydryl buffer to slow down decreases in glutathione and Bcl-xL. In Reg2-/- mice, liver regeneration was markedly impaired, with 29% mortality and delay of the S-phase and the activation of ERK1/2 and AKT. Activation of STAT3 began on time at 3 hours but persisted strongly up to 72 hours despite significant accumulation of SOCS3. Thus, Reg2 deficiency induced exaggerated IL-6/STAT-3 activation and mito-inhibition. Because the Reg2 gene was activated between 6 and 24 hours after hepatectomy in wild-type mice, Reg2 could mediate the TNF-alpha/ IL-6 priming signaling by exerting a negative feed-back on STAT3/ IL-6 activation to allow the hepatocytes to progress through the cell cycle. In conclusion, Reg2 deficiency enhanced liver sensitivity to Fas- induced oxidative stress and delayed liver regeneration with persistent TNF-alpha/ IL6/STAT3 signaling. In contrast, overexpression of human HIP/ PAP promoted liver resistance to Fas and accelerated liver regeneration with early activation/deactivation of STAT3. Reg2/HIP/ PAP is therefore a critical mitogenic and antiapoptotic factor for the liver. (HEPATOLOGY 2006;44:1452-1464.).[1]References
- Reg2 inactivation increases sensitivity to Fas hepatotoxicity and delays liver regeneration post-hepatectomy in mice. Lieu, H.T., Simon, M.T., Nguyen-Khoa, T., Kebede, M., Cortes, A., Tebar, L., Smith, A.J., Bayne, R., Hunt, S.P., Br??chot, C., Christa, L. Hepatology (2006) [Pubmed]
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