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 microg/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.
Lieu
Hanh-Tu
HT
Institut National de la Santé et de la Recherche Médicale, U785, Paris, France.
Simon
Marie-Thérèse
MT
Nguyen-Khoa
Thao
T
Kebede
Messeret
M
Cortes
Alexandre
A
Tebar
Luis
L
Smith
Andrew J H
AJ
Bayne
Rosemary
R
Hunt
Stephen P
SP
Bréchot
Christian
C
Christa
Laurence
L
D000818:Animals; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm / Q000502:physiology; D014408:Biomarkers, Tumor / Q000502:physiology; D056486:Chemical and Drug Induced Liver Injury; D004247:DNA / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006498:Hepatectomy; D006801:Humans; D006834:Hydrazines; D015850:Interleukin-6 / Q000502:physiology; D037181:Lectins, C-Type / Q000502:physiology; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D051058:Oncogene Protein v-akt / Q000502:physiology; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins / Q000502:physiology*; D011719:Pyrazines; D011804:Quinolines; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019014:fas Receptor / Q000502:physiology*
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C491899:Fas protein, mouse; D006834:Hydrazines; D015850:Interleukin-6; D037181:Lectins, C-Type; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; D011719:Pyrazines; C504331:QU663 compound; D011804:Quinolines; C000612141:REG3A protein, human; C490253:Reg3b protein, mouse; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D004247:DNA; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases