TNFα in Liver Fibrosis

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Abstract

Hepatocyte death, inflammation, and liver fibrosis are the hallmarks of chronic liver disease. Tumor necrosis factor-α (TNFα) is an inflammatory cytokine involved in liver inflammation and sustained liver inflammation leads to liver fibrosis. TNFα exerts inflammation, proliferation, and apoptosis. However, the role of TNFα signaling in liver fibrosis is not fully understood. This review highlights the recent findings demonstrating the molecular mechanisms of TNFα and its downstream signaling in liver fibrosis. During the progression of liver fibrosis, hepatic stellate cells play a pivotal role in a dynamic process of production of extracellular matrix proteins and modulation of immune response. Hepatic stellate cells transdifferentiate into activated myofibroblasts in response to damaged hepatocyte-derived mediators and immune cell-derived cytokines/chemokines. Here, we will discuss the role of TNFα in hepatic stellate cell survival and activation and the crosstalk between hepatic stellate cells and hepatocytes or other immune cells, such as macrophages, dendritic cells, and B cells in the development of liver fibrosis.

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Most cited references 44

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Liver fibrosis.

Ramón Bataller, David A. Brenner (2005)

Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation. Our knowledge of the cellular and molecular mechanisms of liver fibrosis has greatly advanced. Activated hepatic stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines such as TGF-beta1, angiotensin II, and leptin. Reversibility of advanced liver fibrosis in patients has been recently documented, which has stimulated researchers to develop antifibrotic drugs. Emerging antifibrotic therapies are aimed at inhibiting the accumulation of fibrogenic cells and/or preventing the deposition of extracellular matrix proteins. Although many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in humans is unknown. This review summarizes recent progress in the study of the pathogenesis and diagnosis of liver fibrosis and discusses current antifibrotic strategies.

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Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes.

Olivier Micheau, Jurg Tschopp (2003)

Apoptosis induced by TNF-receptor I (TNFR1) is thought to proceed via recruitment of the adaptor FADD and caspase-8 to the receptor complex. TNFR1 signaling is also known to activate the transcription factor NF-kappa B and promote survival. The mechanism by which this decision between cell death and survival is arbitrated is not clear. We report that TNFR1-induced apoptosis involves two sequential signaling complexes. The initial plasma membrane bound complex (complex I) consists of TNFR1, the adaptor TRADD, the kinase RIP1, and TRAF2 and rapidly signals activation of NF-kappa B. In a second step, TRADD and RIP1 associate with FADD and caspase-8, forming a cytoplasmic complex (complex II). When NF-kappa B is activated by complex I, complex II harbors the caspase-8 inhibitor FLIP(L) and the cell survives. Thus, TNFR1-mediated-signal transduction includes a checkpoint, resulting in cell death (via complex II) in instances where the initial signal (via complex I, NF-kappa B) fails to be activated.

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Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey.

Bharat B. Aggarwal, Subash C Gupta, Ji Kim (2012)

Although activity that induced tumor regression was observed and termed tumor necrosis factor (TNF) as early as the 1960s, the true identity of TNF was not clear until 1984, when Aggarwal and coworkers reported, for the first time, the isolation of 2 cytotoxic factors: one, derived from macrophages (molecular mass 17 kDa), was named TNF, and the second, derived from lymphocytes (20 kDa), was named lymphotoxin. Because the 2 cytotoxic factors exhibited 50% amino acid sequence homology and bound to the same receptor, they came to be called TNF-α and TNF-β. Identification of the protein sequences led to cloning of their cDNA. Based on sequence homology to TNF-α, now a total of 19 members of the TNF superfamily have been identified, along with 29 interacting receptors, and several molecules that interact with the cytoplasmic domain of these receptors. The roles of the TNF superfamily in inflammation, apoptosis, proliferation, invasion, angiogenesis, metastasis, and morphogenesis have been documented. Their roles in immunologic, cardiovascular, neurologic, pulmonary, and metabolic diseases are becoming apparent. TNF superfamily members are active targets for drug development, as indicated by the recent approval and expanding market of TNF blockers used to treat rheumatoid arthritis, psoriasis, Crohns disease, and osteoporosis, with a total market of more than US $20 billion. As we learn more about this family, more therapeutics will probably emerge. In this review, we summarize the initial discovery of TNF-α, and the insights gained regarding the roles of this molecule and its related family members in normal physiology and disease.