Novel Role of IL-13 in Fibrosis Induced by Nonalcoholic Steatohepatitis and Its Amelioration by IL-13R-Directed Cytotoxin in a Rat Model

Shimamura, Takeshi; Fujisawa, Toshio; Husain, Syed R.; Kioi, Mitomu; Nakajima, Atsushi; Puri, Raj K.

doi:10.4049/jimmunol.181.7.4656

Cited by 78 publications

(85 citation statements)

References 49 publications

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“…Recent studies proved that IL-13 directly mediates production of TGF-b1 via IL-13RaII in HSCs (18). To further investigate whether TGF-b production and release is required for IL-13-induced CTGF expression, we used a TGF-b neutralizing Ab (1D11; Fig.…”

Section: Il-13-induced Ctgf Protein Expression In Hscs Is Tgf-b Indepmentioning

confidence: 99%

“…When IL-4 and IL-13 were inhibited independently, IL-13 was identified as the dominant profibrotic cytokine in several experimental models of fibrosis (7)(8)(9)(14)(15)(16). IL-13 may also serve as a potent activator of TGF-b by upregulating synthesis of proteins that cleave the latency-associated peptide in lung (17) and has been reported to directly induce production of TGF-b1 in HSCs during liver fibrosis (18). In contrast, there is no reduction of liver fibrosis in TGF-b-and Smad3-deficient mice infected with Schistosoma mansoni (19), suggesting that IL-13 may operate independently of TGF-b in fibrogenesis.…”

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confidence: 99%

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IL-13 Induces Connective Tissue Growth Factor in Rat Hepatic Stellate Cells via TGF-β–Independent Smad Signaling

Liu

Meyer

Müller

et al. 2011

The Journal of Immunology

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Connective tissue growth factor (CTGF) plays a central role in stimulating extracellular matrix deposition in the liver, and hence is considered a critical mediator of TGF-β–dependent fibrogenesis. Hepatic stellate cells (HSCs) are known as the major source of CTGF in damaged liver. However, previous studies revealed that IL-13, rather than TGF-β, represents the predominant inducer of CTGF expression in HSCs. We now dissected IL-13 downstream signaling that modulates CTGF expression in HSCs. IL-13 induces a time- and dosage-dependent increase of CTGF in a TGF-β–independent manner. This process requires participation of different Smad proteins and their upstream receptor kinases (activin receptor-like kinases). Smad1 and Smad2 were identified as the key mediators of IL-13–dependent CTGF expression. Furthermore, IL-13 induces Stat6 phosphorylation in HSCs, but Stat6 was not involved in CTGF induction. Instead, the Erk1/2-MAPK pathway was found to be responsible for IL-13–induced early Smad phosphorylation and CTGF synthesis. We demonstrate that IL-13 induces CTGF expression in HSCs by activating TGF-β–independent activin receptor-like kinase/Smad signaling via the Erk-MAPK pathway rather than via its canonical JAK/Stat6 pathway. These results provide an improved new insight into the molecular mechanisms of profibrotic IL-13 activities in the liver.

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Section: Il-13-induced Ctgf Protein Expression In Hscs Is Tgf-b Indepmentioning

confidence: 99%

mentioning

confidence: 99%

IL-13 Induces Connective Tissue Growth Factor in Rat Hepatic Stellate Cells via TGF-β–Independent Smad Signaling

Liu

Meyer

Müller

et al. 2011

The Journal of Immunology

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“…It is known that IL-13 binds to two chains, IL-13Ra1 and IL-13Ra2. IL-13Ra1 chain is a low-affinity receptor that forms a heterodimer with the IL-4Ra chain to form a high-affinity IL-13R and mediates signal transduction through the JAK-STAT-6 pathway (9). IL-13Ra2 chain binds to IL-13 with high affinity but was shown to act as a decoy receptor in mice (10).…”

mentioning

confidence: 99%

IL-13 Immunotoxin Accelerates Resolution of Lung Pathological Changes Triggered by Silica Particles in Mice

Ferreira

Arantes

Nascimento

et al. 2013

The Journal of Immunology

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Instillation of silica into the lungs of rodents results in pathological changes that strongly mimic human silicosis, an occupational lung disease marked by restrictive airway obstruction, inflammation, and fibrosis. Because IL-13 is a pivotal proinflammatory and fibrogenic cytokine, we examined whether a recombinant immunotoxin comprised of human IL-13 and a mutated form of Pseudomonas exotoxin (IL-13–PE) might affect pathological features of experimental silicosis. Mice received a single intranasal instillation of silica particles and were treated with intranasal IL-13–PE every other day from days 21 to 27 postsilica. The sensitivity of putative cell targets to IL-13–PE was also assessed in in vitro settings. Upregulation of IL-13, its receptor subunits IL-13Rα1 and IL-13Rα2, and shared receptor IL-4Rα were associated with development of granulomatous lung inflammation triggered by silica. IL-13–PE inhibited silica-induced granuloma and fibrotic responses noted at 24 h and 15 d after the last treatment. Upregulation of TNF-α, TGF-β, and chemokines, as well as increased collagen deposition and airway hyperreactivity to methacholine were all clearly sensitive to IL-13–PE. In addition, IL-13–PE inhibited both IL-13–induced proliferation of cultured lung fibroblasts from silicotic mice and silica-induced IL-8 generation from A549 cells. In conclusion, our findings show that therapeutic treatment with IL-13–PE can reverse important pathological features caused by inhalation of silica particles, suggesting that this recombinant immunotoxin is a promising molecular template in drug discovery for the treatment of silicosis.

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“…Overproduction of IL-13 might be harmful to the liver, however, because IL-13 is known to directly activate hepatic stellate cells to a fibrogenic phenotype (10). Moreover, strong positive correlations between IL-13 and advanced stages of NAFLD -specifically, steatohepatitis and liver fibrosis -have been reported (11,12). Consistent with that concept, rats with diet-induced steatohepatitis that were treated with an IL-13 receptor-directed cytotoxin showed decreased liver injury and fibrosis (11).…”

Section: A New Role For Il-13mentioning

confidence: 99%

The benefits of restraint: a pivotal role for IL-13 in hepatic glucose homeostasis

Machado¹,

Yang²,

Diehl³

2012

J. Clin. Invest.

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In response to feeding, insulin promotes the uptake of sugar in peripheral tissues and suppresses the production of sugar, a process called gluconeogenesis, in the liver. Recent research has shown that chronic inflammation promotes insulin resistance, and in turn, chronically high glucose levels can drive inflammation. In this issue of the JCI, Stanya et al. investigate the connection between inflammation and glucose homeostasis by analyzing the effect of the antiinflammatory cytokine IL-13. Their results suggest that IL-13 plays an unexpected role in the regulation of glucose homeostasis by modulating gluconeogenesis and may be a useful therapeutic target for treatment of diabetes and metabolic syndrome.Obesity and deregulated glucose metabolism are the pandemic of the twenty-first century. One-fourth of Americans have metabolic syndrome (1), a combination of insulin resistance, obesity, dyslipidemia, and hypertension that in the liver manifests as nonalcoholic fatty liver disease (NAFLD). The liver is believed to play a pivotal role in the pathogenesis of metabolic syndrome because postprandial hyperglycemia is one of the earliest manifestations of this condition. Unlike healthy individuals, those with metabolic syndrome fail to downregulate hepatic gluconeogenesis appropriately after eating. The resultant hyperglycemia stimulates the pancreas to increase insulin secretion. Recurrent hyperinsulinemia results in insulin resistance, and in turn, the excessive demand for insulin production can ultimately overwhelm pancreatic β cell capacity, leading to fasting hyperglycemia, i.e., type 2 diabetes mellitus (T2DM). Data from the Centers for Disease Control show that there has been a 160% increase in the prevalence of T2DM in the past 20 years, such that T2DM now afflicts about 9% of the US population (i.e., more than 20 million Americans; ref. 2). Despite tremendous efforts by the scientific community, the mechanisms that deregulate hepatic glucose metabolism in metabolic syndrome are not fully understood.

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Novel Role of IL-13 in Fibrosis Induced by Nonalcoholic Steatohepatitis and Its Amelioration by IL-13R-Directed Cytotoxin in a Rat Model

Cited by 78 publications

References 49 publications

IL-13 Induces Connective Tissue Growth Factor in Rat Hepatic Stellate Cells via TGF-β–Independent Smad Signaling

IL-13 Induces Connective Tissue Growth Factor in Rat Hepatic Stellate Cells via TGF-β–Independent Smad Signaling

IL-13 Immunotoxin Accelerates Resolution of Lung Pathological Changes Triggered by Silica Particles in Mice

The benefits of restraint: a pivotal role for IL-13 in hepatic glucose homeostasis

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