Roben G. Gieling

Interleukin-1 participates in the progression from liver injury to fibrosis

Interleukin-1 (IL-1) is rapidly expressed in response to tissue damage; however, its role in coordinating the progression from injury to fibrogenesis is not fully understood. Liver fibrosis is a consequence of the activation of hepatic stellate cells (HSCs), which reside within the extracellular matrix (ECM) of subsinusoids. We have hypothesized that, among the hepatic inflammatory cytokines, IL-1 may directly activate HSCs through autocrine signaling and stimulate the matrix metalloproteinases (MMPs) produced by HSCs within the space of Disse, resulting in liver fibrogenesis. In this study, we first established a temporal relationship between IL-1, MMPs, HSC activation, and early fibrosis. The roles of IL-1 and MMP-9 in HSC activation and fibrogenesis were determined by mice deficient of these genes. After liver injury, IL-1, MMP-9, and MMP-13 levels were found to be elevated before the onset of HSC activation and fibrogenesis. IL-1 receptor-deficient mice exhibited ameliorated liver damage and reduced fibrogenesis. Similarly, advanced fibrosis, as determined by type-I and -III collagen mRNA expression and fibrotic septa, was partially attenuated by the deficiency of IL-1. In the early phase of liver injury, the MMP-9, MMP-13, and TIMP-1 expression correlated well with IL-1 levels. In injured livers, MMP-9 was predominantly colocalized to desmin-positive cells, suggesting that HSCs are MMP-producing cells in vivo. MMP-9-deficient mice were partially protected from liver injury and HSC activation. Thus IL-1 is an important participant, along with other cytokines, and controls the progression from liver injury to fibrogenesis through activation of HSCs in vivo.

Fibrosis and Cirrhosis Reversibility – Molecular Mechanisms

The concept that liver fibrosis is a dynamic process with potential for regression as well as progression has emerged in parallel with clinical evidence for remodeling of fibrotic extracellular matrix in patients who can be effectively treated for their underlying cause of liver disease. This article reviews recent discoveries relating to the cellular and molecular mechanisms that regulate fibrosis regression, with emphasis on studies that have used experimental in vivo models of liver disease. Apoptosis of hepatic myofibroblasts is discussed. The functions played by transcription factors, receptor-ligand interactions, and cell-matrix interactions as regulators of the lifespan of hepatic myofibroblasts are considered, as are the therapeutic opportunities for modulating these functions. Growth factors, proteolytic enzymes, and their inhibitors are discussed in detail.

NF-κB is a critical regulator of the survival of rodent and human hepatic myofibroblasts☆

BACKGROUND/AIMS Hepatic myofibroblast activation during injury causes deposition of extracellular matrix within the liver and promotes development of fibrosis. Hepatic myofibroblast apoptosis is associated with remodelling of fibrotic extracellular matrix and regression of fibrosis. Previous work showed that inhibition of constitutive NF-kappaB signaling promotes hepatic myofibroblast apoptosis and resolution of fibrosis in rodent models. However, to date agents used to target constitutive NF-kappaB transcriptional activity in hepatic myofibroblasts have been relatively non-specific with potential for off-target effects that may complicate data interpretation. Likewise, rat chronic liver disease models may not accurately recapitulate the activation of human hepatic myofibroblasts. METHODS We used a mutant recombinant IkappaBalpha super-repressor fused to the HIV-TAT domain to specifically target NF-kappaB signaling in hepatic myofibroblasts. Inhibition of NF-kappaB activity was measured using reporter assay. Apoptosis of hepatic myofibroblasts was assessed by morphological changes, cleavage of the PARP-1 protein and Caspase 3 activation. RESULTS TAT-IkappaBalphaSR reduced NF-kappaB dependent transcription, Bcl-2 expression and promoted Jun-N-terminal kinase-dependent apoptosis in human and rat hepatic myofibroblasts. CONCLUSIONS These data highlight the conserved role of NF-kappaB during fibrogenesis. Our data validate the use of rodent models for pre-clinical testing of NF-kappaB inhibitors as anti-fibrotics and stimulators of fibrotic extracellular matrix remodelling.

The c-rel subunit of nuclear factor-κb regulates murine liver inflammation, wound-healing, and hepatocyte proliferation

In this study, we determined the role of the nuclear factor‐kappaB (NF‐κB) subunit c‐Rel in liver injury and regeneration. In response to toxic injury of the liver, c‐Rel null (c‐rel−/−) mice displayed a defect in the neutrophilic inflammatory response, associated with impaired induction of RANTES (Regulated upon Activation, Normal T‐cell Expressed, and Secreted; also known as CCL5). The subsequent fibrogenic/wound‐healing response to both chronic carbon tetrachloride and bile duct ligation induced injury was also impaired and this was associated with deficiencies in the expression of fibrogenic genes, collagen I and α‐smooth muscle actin, by hepatic stellate cells. We additionally report that c‐Rel is required for the normal proliferative regeneration of hepatocytes in response to toxic injury and partial hepatectomy. Absence of c‐Rel was associated with blunted and delayed induction of forkhead box M1 (FoxM1) and its downstream targets cyclin B1 and Cdc25C. Furthermore, isolated c‐rel−/− hepatocytes expressed reduced levels of FoxM1 and a reduced rate of basal and epidermal growth factor–induced DNA synthesis. Chromatin immunoprecipitation revealed that c‐Rel binding to the FoxM1 promoter is induced in the regenerating liver. Conclusion: c‐Rel has multiple functions in the control of liver homeostasis and regeneration and is a transcriptional regulator of FoxM1 and compensatory hepatocyte proliferation. (HEPATOLOGY 2010.)