Interferon gamma‐1b for the treatment of fibrosis in chronic hepatitis C infection

Muir, Andrew J.; Sylvestre, Pamela B.; Rockey, Don C.

doi:10.1111/j.1365-2893.2005.00689.x

Cited by 58 publications

(40 citation statements)

References 49 publications

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“…Abundant evidence links IFN␥ to fibrogenesis, and this cytokine has been proposed as a putative therapy for fibrosis (17,30,31). In the wounding milieu, IFN␥ exhibits prominent inhibitory effects on fibroblasts and myofibroblasts, including hepatic stellate cells, liver-specific myofibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Interferon-γ-mediated Inhibition of Serum Response Factor-dependent Smooth Muscle-specific Gene Expression

Shi

Rockey

2010

Journal of Biological Chemistry

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IFN␥ exerts multiple biological effects on effector cells by regulating many downstream genes, including smooth muscle-specific genes. However, the molecular mechanisms underlying IFN␥-induced inhibition of smooth muscle-specific gene expression remain unclear. In this study, we have shown that serum response factor (SRF), a common transcriptional factor important in cell proliferation, migration, and differentiation, is targeted by IFN␥ in a STAT1-dependent manner. We show that the molecular mechanism by which IFN␥ regulates SRF is via activation of the 2-5A-RNase L system, which triggers SRF mRNA decay and reduced SRF expression. As a result, decreased SRF expression reduces expression of SRF target genes such as smooth muscle ␣-actin and smooth muscle myosin heavy chain. Additionally, IFN␥ reduced p300 and acetylated histone-3 binding in both smooth muscle ␣-actin and SRF promoters, epigenetically decreasing smooth muscle ␣-actin and SRF transcriptional activation. Our data reveal that SRF is a novel IFN␥-regulated gene and further elucidate the molecular pathway between IFN␥, IFN␥-regulated genes, and SRF and its target genes.IFN␥, a pleiotropic cytokine that is primarily produced by T cells and NK cells, plays a complex and central role in antiviral, antiproliferative, antifibrogenesis, antitumor, and immunomodulatory activities (reviewed in Refs. 1 and 2). The complexity of such a variety of IFN␥ effects appears to be achieved by its signaling to over 200 genes, leading to a highly networked pattern of cell-specific gene regulation (3). In the canonical pathway, through binding to cognate IFN type II receptors, IFN␥ initiates a cascade that includes JAK family kinases and the STAT1 family of transcriptional factors to induce STAT1-dependent gene expression, which largely mediates the actions of IFN␥ (reviewed in Ref. 4). Among IFN␥-regulated genes, smooth muscle ␣-actin, a cytoskeleton protein that is critical in smooth muscle cell differentiation (reviewed in Ref. 5), myofibroblast activation (reviewed in Ref. 6), and epithelial-mesenchymal transition (7), is negatively regulated by IFN␥ (8, 9). Although the observation that IFN␥ regulates smooth muscle ␣-actin is well established, the molecular mechanisms underlying IFN␥-induced inhibition of smooth muscle ␣-actin expression remain unclear.Regulation of smooth muscle ␣-actin expression is complex, having been studied extensively in cardiovascular and vascular diseases, particularly in smooth muscle cells (reviewed in Ref. 5). It has been well demonstrated that most muscle-specific genes, including smooth muscle ␣-actin, are SRF 2 target genes. SRF binds to the CArG boxes (CC(A/T) 6 GG) of the smooth muscle ␣-actin gene promoter and activates smooth muscle ␣-actin transcription (reviewed in Ref. 10). Extracellular factors can exert their effects on smooth muscle gene expression through regulating SRF or/and SRF cofactors (11). TGF␤, a well characterized cytokine important in smooth muscle cell differentiation and epithelial-mesenchymal transition, up-reg...

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Section: Discussionmentioning

confidence: 99%

Interferon-γ-mediated Inhibition of Serum Response Factor-dependent Smooth Muscle-specific Gene Expression

Shi

Rockey

2010

Journal of Biological Chemistry

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“…IFN-g has been ascribed antifibrotic properties based largely on in vitro studies of reduced collagen production by fibroblasts (34)(35)(36), but these have not translated to successful therapy in patients (37). Conversely, the emergence of skin lesions in subsets of hepatitis C patients receiving IFN-a therapies has suggested a profibrotic role for type I IFNs (38,39). Our data build on these observations and suggest a key role for type I IFNs in promoting skin fibrosis; the relative importance of IFN-a compared with IFN-b, however, requires further clarification via isoform-specific neutralizing Abs.…”

Section: Discussionmentioning

confidence: 99%

Type I IFNs Regulate Inflammation, Vasculopathy, and Fibrosis in Chronic Cutaneous Graft-versus-Host Disease

Delaney¹,

Morehouse²,

Brohawn³

et al. 2016

The Journal of Immunology

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Type I IFNs play a critical role in the immune response to viral infection and may also drive autoimmunity through modulation of monocyte maturation and promotion of autoreactive lymphocyte survival. Recent demonstrations of type I IFN gene signatures in autoimmune diseases, including scleroderma, led us to investigate the pathological role of IFNs in a preclinical model of sclerodermatous graft-versus-host disease. Using a neutralizing Ab against the type I IFN receptor IFNAR1, we observed a marked reduction in dermal inflammation, vasculopathy, and fibrosis compared with that seen in the presence of intact IFNAR1 signaling. The ameliorative effects of IFNAR1 blockade were restricted to the skin and were highly associated with inhibition of chronic vascular injury responses and not due to the inhibition of the T or B cell alloresponse. Inhibition of IFNAR1 normalized the overexpression of IFN-inducible genes in graft-versus-host disease skin and markedly reduced dermal IFN-α levels. Depletion of plasmacytoid dendritic cells, a major cellular source of type I IFNs, did not reduce the severity of fibrosis or type I IFN gene signature in the skin. Taken together, these studies demonstrate an important role for type I IFN in skin fibrosis, and they provide a rationale for IFNAR1 inhibition in scleroderma.

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“…23 In line with this, IFN-␥ displayed a therapeutic effect in patients with chronic hepatitis B virus (HBV) 24 and hepatitis C virus infections. 25 In this study, we show for the first time that in a damaged liver, TGF-␤ provides profibrogenic signals in hepatocytes via activin receptor-like kinase 5 (ALK5)/RSmad-dependent induction of CTGF expression, a mechanism appearing similarly in animal models and human patients. Furthermore, we show that the abrogation of TGF-␤ signaling by Smad7 or IFN-␥ decreases the expression of profibrogenic CTGF.…”

mentioning

confidence: 98%

Profibrogenic transforming growth factor-β/activin receptor–like kinase 5 signaling via connective tissue growth factor expression in hepatocytes

et al. 2007

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Connective tissue growth factor (CTGF) is important for transforming growth factor-␤ (TGF-␤)-induced liver fibrogenesis. Hepatic stellate cells have been recognized as its major cellular source in the liver. Here we demonstrate the induction of CTGF expression in hepatocytes of damaged livers and identify a molecular mechanism responsible for it. CTGF expression was found by immunohistochemistry in bile duct epithelial cells, hepatic stellate cells, and hepatocytes in fibrotic liver tissue from patients with chronic hepatitis B infection. Similarly, CTGF expression was induced in hepatocytes of carbon tetrachloride-treated mice. CTGF expression and secretion were detected spontaneously in a medium of hepatocytes after 3 days of culture, which was enhanced by stimulation with TGF-␤. TGF-␤-induced CTGF expression was mediated through the activin receptor-like kinase 5 (ALK5)/ Smad3 pathway, whereas activin receptor-like kinase 1 activation antagonized this effect. CTGF expression in the liver tissue of TGF-␤ transgenic mice correlated with serum TGF-␤ levels. Smad7 overexpression in cultured hepatocytes abrogated TGF-␤-dependent and intrinsic CTGF expression, indicating that TGF-␤ signaling was required. In line with these data, hepatocyte-specific transgenic Smad7 reduced CTGF expression in carbon tetrachloride-treated animals, whereas in Smad7 knockout mice, it was enhanced. Furthermore, an interferon gamma treatment of patients with chronic hepatitis B virus infection induced Smad7 expression in hepatocytes, leading to decreased CTGF expression and fibrogenesis. Conclusion: Our data provide evidence for the profibrogenic activity of TGF-␤ directed to hepatocytes and mediated via the up-regulation of CTGF. We identify ALK5-dependent Smad3 signaling as the responsible pathway inducing CTGF expression, which can be hindered by an activated activin receptor-like kinase 1 pathway and completely inhibited by

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Interferon gamma‐1b for the treatment of fibrosis in chronic hepatitis C infection

Cited by 58 publications

References 49 publications

Interferon-γ-mediated Inhibition of Serum Response Factor-dependent Smooth Muscle-specific Gene Expression

Interferon-γ-mediated Inhibition of Serum Response Factor-dependent Smooth Muscle-specific Gene Expression

Type I IFNs Regulate Inflammation, Vasculopathy, and Fibrosis in Chronic Cutaneous Graft-versus-Host Disease

Profibrogenic transforming growth factor-β/activin receptor–like kinase 5 signaling via connective tissue growth factor expression in hepatocytes

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