Liver regeneration induced by a designer human IL‐6/ sIL‐6R fusion protein reverses severe hepatocellular injury

Galun, Eithan; Zeira, Evelyn; Pappo, Orit; Peters, Malte; Rose-John, Stefan

doi:10.1096/fj.99-0913com

Cited by 114 publications

(75 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…28 For instance, administration of IL-6 potently reverses hepatocellular injury. 39 IL-6 also has been reported to restore metabolic function and to improve ATP levels after reperfusion injury and extreme hepatectomy. 40 The observations are therefore in line with our finding of higher TNF-␣ and IL-6 levels in patients recovering spontaneously from ALF compared with those who failed to recover.…”

Section: Discussionmentioning

confidence: 99%

Caspase activation is associated with spontaneous recovery from acute liver failure

et al. 2008

View full text Add to dashboard Cite

Acute liver failure (ALF) has various causes and is characterized by rapid hepatocyte dysfunction with development of encephalopathy in the absence of preexisting liver disease. Whereas most patients require liver transplantation to prevent the high mortality, some patients recover spontaneously and show complete liver regeneration. Because of the low incidence of ALF, however, the molecular mechanisms of liver dysfunction and regeneration are largely unknown. In this study, we investigated the role of apoptosis and caspases in 70 ALF patients using novel biomarkers that allow the detection of caspase activation in serum samples. Compared with healthy individuals, activation of caspases was strongly enhanced in ALF patients. Interestingly, patients with spontaneous recovery from ALF revealed a significantly higher activation of caspases than patients that required transplantation or died, although in the latter patients extensive DNA fragmentation and signs of nonapoptotic cell death were observed. In the spontaneous survivors, increased caspase activation was accompanied by elevated levels of tumor necrosis factor alpha (TNF-␣) and interleukin-6 (IL-6), important cytokines involved in liver regeneration. Conclusion: Our data suggest that caspase activation and apoptosis are involved in ALF of patients with spontaneous recovery, whereas caspase-independent cell death might be more relevant in irreversible forms of liver failure. These findings might be important for therapeutic options of ALF but also suggest that measurement of caspase activation might be of prognostic value to predict the outcome of acute liver failure. (HEPATOLOGY 2008;47:1624-1633

show abstract

Section: Discussionmentioning

confidence: 99%

Caspase activation is associated with spontaneous recovery from acute liver failure

et al. 2008

View full text Add to dashboard Cite

show abstract

“…30,31 Liver regeneration is enhanced by a designer IL-6/soluble IL-6 receptor fusion protein with superagonistic IL-6 properties or upon overexpression of STAT3. 32,33 In addition, IL-6 prevents mortality following fatty liver transplants in rats. 34 These results indicate that A20 is either "the" NF-Bdependent gene required for liver regeneration or that other NF-B-independent proliferative pathways triggered by TNF and IL-6 are enabled in hepatocytes expressing A20.…”

Section: Discussionmentioning

confidence: 99%

A20 protects mice from lethal radical hepatectomy by promoting hepatocyte proliferation via a p21waf1-dependent mechanism

Longo¹,

Patel²,

Shrikhande³

et al. 2005

Hepatology

View full text Add to dashboard Cite

The liver has a remarkable regenerative capacity, allowing recovery following injury. Regeneration after injury is contingent on maintenance of healthy residual liver mass, otherwise fulminant hepatic failure (FHF) may arise. Understanding the protective mechanisms safeguarding hepatocytes and promoting their proliferation is critical for devising therapeutic strategies for FHF. We demonstrate that A20 is part of the physiological response of hepatocytes to injury. In particular, A20 is significantly upregulated in the liver following partial hepatectomy. A20 protects hepatocytes from apoptosis and ongoing inflammation by inhibiting NF-B. Hepatic expression of A20 in BALB/c mice dramatically improves survival following extended and radical lethal hepatectomy. A20 expression in the liver limits hepatocellular damage hence maintains bilirubin clearance and the liver synthetic function. In addition, A20 confers a proliferative advantage to hepatocytes via decreased expression of the cyclin-dependent kinase inhibitor p21 waf1 . In conclusion, A20 provides a proliferative advantage to hepatocytes. By combining anti-inflammatory, antiapoptotic and pro-proliferative functions, A20-based therapies could be beneficial in prevention and treatment of FHF. (HEPATOLOGY 2005;42:156-164.)

show abstract

“…Because new IL-6/gp130-dependent treatment approaches are effective in different forms of acute liver injury, 45,46 it might be possible that specific delivery to a given target cell in chronic forms of liver injury could be an attractive molecular-based therapy.…”

Section: Discussionmentioning

confidence: 99%

Interleukin 6/gp130-dependent pathways are protective during chronic liver diseases

et al. 2003

View full text Add to dashboard Cite

The contribution of the acute phase inducer interleukin 6 (IL-6) in the pathogenesis of liver diseases is yet unclear. Our analysis showed enhanced expression of IL-6 in livers derived from patients with acute and chronic liver diseases. Additionally, IL-6 plasma levels were significantly increased in patients with chronic liver diseases and showed an inverse correlation with biochemical markers of liver function and a positive correlation with inflammatory markers, signs of portal hypertension, and the degree of liver fibrosis. To prove the relevance of these clinical findings, we applied the tetrachlorcarbonide (CCl 4 ) model to conditional knockout animals (Cre/loxP system) for gp130, the common signal transducer of IL-6 family cytokines. Cre recombinases were expressed through a hepatocyte (AlfpCre) and a ubiquitous (MxCre) control element. Gp130 deleted mice had a totally abolished STAT3 activation and acute phase response induction, but gp130 deletion had no effect on the degree of acute liver injury and subsequent hepatocyte proliferation. In contrast, during chronic liver injury induced by biweekly application of CCl 4 , deletion of the gp130 receptor in nonparenchymal liver cells and not hepatocytes resulted in fibrosis progression. In conclusion, our experiments indicate an involvement of IL-6 in the pathogenesis of liver diseases and suggest a protective role of IL-6/gp130-dependent pathways in nonparenchymal liver cells during fibrosis progression in chronic liver diseases. (HEPATOLOGY 2003;38:218-229.)

show abstract

Liver regeneration induced by a designer human IL‐6/ sIL‐6R fusion protein reverses severe hepatocellular injury

Cited by 114 publications

References 35 publications

Caspase activation is associated with spontaneous recovery from acute liver failure

Caspase activation is associated with spontaneous recovery from acute liver failure

A20 protects mice from lethal radical hepatectomy by promoting hepatocyte proliferation via a p21waf1-dependent mechanism

Interleukin 6/gp130-dependent pathways are protective during chronic liver diseases

Contact Info

Product

Resources

About