Keratinocyte growth factor protects murine hepatocytes from tumor necrosis factor-induced apoptosis in vivo and in vitro

Abstract

Keratinocyte growth factor (KGF) promotes epithelial growth and differentiation and has potent effects on the liver. The coinjection of lipopolysaccharide (LPS) and D-galactosamine (GalN) results in hepatic failure in mice. Mechanistically, LPS-induced tumor necrosis factor (TNF) triggers hepatocyte apoptosis, which is enhanced by GalNarrested transcription. Similarly, the combination of TNF and actinomycin D (ActD) causes hepatocyte apoptosis in vitro. We studied the effect of KGF on LPS and GalNinduced hepatic failure in vivo and on TNF-and ActDinduced hepatocyte apoptosis in vitro, where it was compared with those of hepatic growth factor (HGF) and epidermal growth factor (EGF). Mice treated with human recombinant KGF (1 mg/kg subcutaneously) 24 hours before intraperitoneal coinjection of LPS and GalN sustained prolonged survival compared with control mice, although overall mortality was not changed. The counts of apoptotic hepatocytes, serum alanine and aspartate transaminases, and DNA fragments in the cytosolic fraction of liver homogenates were higher in control mice than in treated mice 6 hours after LPS and GalN coinjection, before any mortality occurred. In vitro, hepatocytes pretreated with KGF exhibited reduced TNF-and ActD-induced cell damage and DNA fragmentation, similar to hepatocytes pretreated with HGF and EGF. In conclusion, KGF prolongs survival during LPS-and GalN-induced hepatic failure by temporarily protecting hepatocytes against apoptosis. It also protects hepatocytes in vitro against TNF-and ActDinduced apoptosis. (HEPATOLOGY 1998;27:1584-1591.)

Keratinocyte growth factor and beta-cell differentiation in human fetal pancreatic endocrine precursor cells

“…Recent studies have shown an anti-apoptotic effect of KGF on various tissues such as epidermal cells [29], neural cells [30] and hepatocytes [31]. In this study KGF could have exerted such a role on transplanted cells in the early days after transplantation, a time at which some loss of tissue is known to occur [32].…”

Liposomal gene transfer of multiple genes is more effective than gene transfer of a single gene

“…12 After wounding, KGF protein and mRNA concentration increases and they are mainly present in the dermal fibroblasts below the wound and at the wound edges, whereas KGF receptor transcripts and also the corresponding protein were exclusively detected in keratinocytes of the epidermis and the hair follicles. 17 These cells migrate over the wound and subsequently proliferate, which leads to complete wound re-epithelization. Conforming to previous experiments, we showed in the present study that the gene transfer of IGF-I cDNA and KGF cDNA individually demonstrated the same effects as previously shown.…”

“…14 Moreover, KGF stimulates proliferation and exerts an antiapoptotic effect for epithelial cells, which are of major importance for the post-traumatic wound healing. [15][16][17] Another growth factor that was found to be effective in the wound healing process is IGF-I. IGF-I, a protein of 7.7 kDa, is a mesenchymal growth factor that accelerates wound healing by stimulating collagen synthesis and the mitogenicity of fibroblasts and keratinocytes.…”

Fibroblast growth factor receptor signalling is crucial for liver homeostasis and regeneration

“…However, until now, little is known about the function of FGFs in liver homeostasis postnatally, and a role of FGFs in liver repair has not been demonstrated. Since FGF7 is a potent mitogen for hepatocytes in vitro and in vivo (Housley et al, 1994;Strain et al, 1994) and since it can protect hepatocytes from tumor necrosis factor-induced apoptosis (Senaldi et al, 1998), we speculated about a role of FGFs in liver homeostasis and regeneration. To address this question, we chose to express a dominant-negative FGFR mutant in hepatocytes.…”