The role of cytokines in liver failure and regeneration: potential new molecular therapies

Abstract

The liver is a unique organ, and first in line, the hepatocytes encounter the potential to proliferate during cell mass loss. This phenomenon is tightly controlled and resembles in some way the embryonal co-inhabitant cell lineage of the liver, the embryonic hematopoietic system. Interestingly, both the liver and hematopoietic cell proliferation and growth are controlled by various growth factors and cytokines. IL-6 and its signaling cascade inside the cells through STAT3 are both significantly important for liver regeneration as well as for hematopoietic cell proliferation. The process of liver regeneration is very complex and is dependent on the etiology and extent of liver damage and the genetic background. In this review we will initially describe the clinical relevant condition, portraying a number of available animal models with an emphasis on the relevance of each one to the human condition of fulminant hepatic failure (FHF). The discussion will then be focused on the role of cytokines in liver failure and regeneration, and suggest potential new therapeutic modalities for FHF. The recent findings on the role of IL-6 in liver regeneration and the activity of the designer IL-6/sIL-6R fusion protein, hyper-IL-6, in particular, suggest that this molecule could significantly enhance liver regeneration in humans, and as such could be a useful treatment for FHF in patients.

Novel Role for Amphiregulin in Protection from Liver Injury

“…The identification of endogenous protective mechanisms triggered upon liver injury is important not only for the study of the pathophysiology of this organ, but also for the design of more effective therapies that potentiate the natural defensive responses (13,24,56). The EGF-R is highly expressed in the hepatocyte and seems to be a relevant mediator of survival and proliferative responses (18 -20, 25-27).…”

“…The identification of agents that reduce hepatocellular apoptosis is thus of special significance for the development of hepatoprotective therapeutics (12,13). Intensive research in this area has shown that cytokines such as interleukin-6 (IL-6), 1 growth factors like hepatocyte growth factor, or the hepatocyte-derived insulin-like growth factor binding protein-1 display potent hepatoprotective effects, including the attenuation of apoptosis induced by Fas ligation (14 -17).…”

CD154-CD40 interactions drive hepatocyte apoptosis in murine fulminant hepatitis

“…[1][2][3] It is unclear why some patients develop FH while others exposed to the same hepatic insult do not.…”

Lack of Chemokine Receptor CCR5 Promotes Murine Fulminant Liver Failure by Preventing the Apoptosis of Activated CD1d-Restricted NKT Cells

“…F ulminant liver failure (FLF) 3 is a devastating liver disease that is associated with significant mortality (40 -80%) worldwide (1-3). The incidence of FLF has increased in the last decade accounting for Ͼ2000 deaths annually in the United States alone (2) and represents the reason for 11 and 30% of all liver transplants in Europe and the United States, respectively (1)(2)(3).…”

“…The incidence of FLF has increased in the last decade accounting for Ͼ2000 deaths annually in the United States alone (2) and represents the reason for 11 and 30% of all liver transplants in Europe and the United States, respectively (1)(2)(3). FLF is a clinical syndrome that is characterized by the sudden onset of severe acute hepatitis with associated symptoms, including jaundice and hepatic encephalopathy in a patient with no previous history of liver disease (2,3). Viruses, drugs (such as acetaminophen), and toxins have all been identified as trigger factors of FLF (2, 3); however, in many patients (ϳ20%), the etiology of FLF remains unknown (1).…”