Reg2 inactivation increases sensitivity to Fas hepatotoxicity and delays liver regeneration post-hepatectomy in mice

Abstract

Reg2/RegIII␤ 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 g/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-␣/IL-6 priming signaling by exerting a negative feedback 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-␣/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 F as/FasL (APO-1, CD95) interaction is involved in many pathological situations such as graft-versushost disease, liver transplant and major surgical resection, hepatitis B and C, acute alcoholic hepatitis, drug overdose, and some biliary diseases. Fas activation-induced acute liver failure is characterized by massive hepatic necrosis/apoptosis. Survival of patients depends on the speed with which quiescent liver cells re-enter the cell

Deletion of the mouse RegIIIβ (Reg2) gene disrupts ciliary neurotrophic factor signaling and delays myelination of mouse cranial motor neurons

“…The generation of these mice has been described elsewhere (18). Complete knockout of the gene was confirmed in nervous tissue with immunocytochemistry by using antibodies generated against rat Reg2 protein, and absence of RegIII␤ mRNA was confirmed by using real-time PCR in brain, pancreas, and regenerating liver (16,18).…”

“…First identified as a transcript up-regulated in pancreatitis, Reg2, a secreted protein (relative M r 16,000) found in many sites throughout the body, was shown to have an anti-apoptotic action on pancreatic cell lines (14). Reg2 also promotes the growth of epithelial intestinal cells, whereas loss of Reg2/RegIII␤ delayed liver regeneration (10,(15)(16)(17)(18).…”

Effects of Reg‐2 on Survival of Spinal Cord Neurons In Vitro

“…It is a small (16 kDa) secretory protein induced during acute pancreatitis but not normally expressed in the healthy tissue (Iovanna et al, 1991). PAP was considered to play a role as an hepatic cytokine involved in hepatic proliferation and survival and also in liver regeneration (Iovanna et al, 1991;Orelle et al, 1992;Ortiz et al, 1998;Malka et al, 2000;Lieu et al, 2007). PAP also has antibacterial and antiapoptotic properties, which can against pancreatitis and liver injury (Terazono et al, 1988;Simon et al, 2003).…”

Reg-II Is an Exocrine Pancreas Injury-Response Product That Is Up-Regulated by Keratin Absence or Mutation

“…For example, mice express one type I and one type II members (termed Reg-I and Reg-II, respectively), whereas humans express two type I Regs (Reg-I␣ and Reg-I␤), but no type II (i.e., Reg-II) counterpart (De Reggi and Gharib, 2001;Zhang et al, 2004). The literature pertaining to the nomenclature of the Reg family members is not uniform, because some published work refers to mouse Reg-II when in fact the study pertains to Reg-III␤, which is also termed pancreatitis-associated protein I (Unno et al, 1993;Graf et al, 2006;Lieu et al, 2006). Reg-I and Reg-II are independent gene products but highly homologous proteins sharing 76% amino acid sequence identity, and they are found predominantly in the exocrine pancreas under basal conditions (Unno et al, 1993).…”

“…In mouse liver, mRNA for Reg-II was detected at low levels (Unno et al, 1993), but we do not detect Reg-II protein after immunoblotting of WT or K8-null mouse livers (data not shown). However, Reg-III␤ is expressed in the liver and Reg-III␤-null mice have an increased susceptibility to Fas-mediated liver injury and impairment in liver regeneration after partial hepatectomy (Lieu et al, 2006). Together, with the already known effects of other Regs, our results suggest that Reg-II overexpression is likely to compensate for the lack of K8 and might account, at least in part, to the differences in susceptibility of keratin-deficient mice to liver and pancreatic injury.…”