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      Cytokines and STATs in Liver Fibrosis

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          Abstract

          Liver fibrosis, or cirrhosis, is a common end-stage condition of many chronic liver diseases after incomplete recovery from hepatocyte damage. During fibrosis progression, hepatocellular damage and inflammation trigger complex cellular events that result in collagen deposition and the disruption of the normal liver architecture. Hepatic stellate cell activation and transdifferentiation into myofibroblasts are key events in liver fibrogenesis. Research findings from cell culture and animal models have revealed that the Janus kinase-signal transducer and activator of transcription (Jak-STAT) signaling pathway, which can be activated by many cytokines, growth factors, and hormones, plays a critical role in hepatic fibrogenesis. This review summarizes the biological significance of diverse cytokines and their downstream signaling protein STATs in hepatic fibrogenesis.

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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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            Mechanisms of hepatic fibrogenesis.

            Scott Friedman (2008)
            Substantial improvements in the treatment of chronic liver disease have accelerated interest in uncovering the mechanisms underlying hepatic fibrosis and its resolution. Activation of resident hepatic stellate cells into proliferative, contractile, and fibrogenic cells in liver injury remains a dominant theme driving the field. However, several new areas of rapid progress in the past 5-10 years also have taken root, including: (1) identification of different fibrogenic populations apart from resident stellate cells, for example, portal fibroblasts, fibrocytes, and bone-marrow-derived cells, as well as cells derived from epithelial mesenchymal transition; (2) emergence of stellate cells as finely regulated determinants of hepatic inflammation and immunity; (3) elucidation of multiple pathways controlling gene expression during stellate cell activation including transcriptional, post-transcriptional, and epigenetic mechanisms; (4) recognition of disease-specific pathways of fibrogenesis; (5) re-emergence of hepatic macrophages as determinants of matrix degradation in fibrosis resolution and the importance of matrix cross-linking and scar maturation in determining reversibility; and (6) hints that hepatic stellate cells may contribute to hepatic stem cell behavior, cancer, and regeneration. Clinical and translational implications of these advances have become clear, and have begun to impact significantly on the management and outlook of patients with chronic liver disease.
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              Anti-IL-4 treatment of Schistosoma mansoni-infected mice inhibits development of T cells and non-B, non-T cells expressing Th2 cytokines while decreasing egg-induced hepatic fibrosis.

              F Finkelman, R Seder, Matthew Wynn … (1994)
              Increasing evidence suggests that schistosome egg granulomas are primarily Th2 cellular reactions. Mice infected with Schistosoma mansoni were treated with a neutralizing mAb against IL-4 to evaluate the role of this cytokine in the generation of parasite egg-induced cell-mediated responses and hepatic pathology. Animals treated with anti-IL-4 before egg deposition showed decreased IL-4, IL-5, and IL-10 production in response to in vitro antigenic stimulations and decreased IL-5 and IL-13 mRNA levels in the liver. As observed previously, non-B, non-T cells were a major source of IL-4 in infected mice treated with control mAb, and the diminished IL-4 response in anti-IL-4-treated animals was shown to be caused at least in part by a reduction in the number of these cells, as well as by decreased secretion of IL-4 per cell. In contrast, production of the Th1 cytokines IL-2 and IFN-gamma was elevated in anti-IL-4-treated infected mice in vitro, and the corresponding mRNAs in the liver were increased. Anti-IL-4 treatment did not consistently reduce the size of hepatic granulomas around S. mansoni eggs, but markedly inhibited granuloma formation in the lungs of the same animals after i.v. egg injection. Nevertheless, anti-IL-4-treated infected mice showed consistent and marked reductions in hepatic collagen deposition. These findings indicate that IL-4 plays a major role in the development of the Th2 response in S. mansoni-infected mice and contributes to the pathogenesis of hepatic fibrosis.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Front Physiol
                Journal ID (iso-abbrev): Front Physiol
                Journal ID (publisher-id): Front. Physio.
                Title: Frontiers in Physiology
                Publisher: Frontiers Research Foundation
                ISSN (Electronic): 1664-042X
                Publication date (Electronic preprint): 18 January 2012
                Publication date (Electronic): 03 April 2012
                Publication date Collection: 2012
                Volume: 3
                Electronic Location Identifier: 69
                Affiliations
                [1] 1simpleLaboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health Bethesda, MD, USA
                [2] 2simpleDepartment of Medicine and Molecular Science, Gunma University Graduate School of Medicine Gunma, Japan
                Author notes

                Edited by: Honglei Weng, University of Heidelberg, Germany

                Reviewed by: Honglei Weng, University of Heidelberg, Germany; Robert Eferl, Medical University Vienna, Austria

                *Correspondence: Bin Gao, Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Room 2S-33, Bethesda, MD 20892, USA. e-mail: bgao@ 123456mail.nih.gov

                This article was submitted to Frontiers in Gastrointestinal Sciences, a specialty of Frontiers in Physiology.

                Article
                DOI: 10.3389/fphys.2012.00069
                PMC ID: 3318231
                PubMed ID: 22493582
                SO-VID: 8849d7c4-28cd-4717-a0b1-f3308fe280a8
                Copyright © Copyright © 2012 Kong, Horiguchi, Mori and Gao.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.

                History
                Date received : 03 January 2012
                Date accepted : 11 March 2012
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 86, Pages: 7, Words: 7191
                Categories
                Subject: Physiology
                Subject: Review Article

                ScienceOpen disciplines: Anatomy & Physiology
                Keywords: stellate cells,stats,interferon,interleukin
                Data availability:
                ScienceOpen disciplines: Anatomy & Physiology
                Keywords: stellate cells, stats, interferon, interleukin

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