IL-4 and IL-13 induce myofibroblastic phenotype of human lung fibroblasts through c-Jun NH2-terminal kinase–dependent pathway

Hashimoto, Shigeo; Gon, Yasuhiro; Takeshita, Ikuko; Maruoka, Shuichiro; Horie, Takashi

doi:10.1067/mai.2001.114702

Cited by 133 publications

(98 citation statements)

References 46 publications

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“…We found that fibrocytes cultured for 6 days in SFM alone were able to grow and constitutively produce fibronectin and collagen III with a pattern similar to mature lung fibroblasts (44,46). Upon stimulation with either ET-1 or TGF-␤1, their proliferation rate increased, and they showed multiple markers of differentiation into myofibroblasts (15,19,20,43,44). In particular, they developed bundles of actin microfilaments indicative of a contractile phenotype and produced increased amounts of fibronectin and collagen III.…”

Section: Discussionmentioning

confidence: 99%

“…In another set of experiments we therefore evaluated whether human circulating fibrocytes can differentiate into myofibroblast-like cells under the influence of two fibrogenic cytokines, ET-1 and TGF-␤1, that fare known to function as important myofibroblast promoters (15,19,20,43,44) and are released in exaggerated quantities in the airways of asthmatic patients (30, 31, 40 -42). We found that fibrocytes cultured for 6 days in SFM alone were able to grow and constitutively produce fibronectin and collagen III with a pattern similar to mature lung fibroblasts (44,46).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies (21,22) have described a population of circulating cells, termed fibrocytes, that express fibroblast products as well as the hemopoietic stem cell Ag CD34, enter sites of tissue injury, and localize to areas of extracellular matrix deposition. In culture they acquire structural and functional properties (21-23) similar to those described for myofibroblasts (18,19,24). We hypothesized that fibrocytes represent the circulating precursors of bronchial myofibroblasts and are involved in the genesis of subepithelial fibrosis in asthma.…”

Section: Identification Of Circulating Fibrocytes As Precursors Of Brmentioning

confidence: 99%

“…Although it has been proposed that myofibroblasts originate from airway resident cells, particularly tissue fibroblasts or myocytes (15)(16)(17)(18)(19)(20), there may be a circulating precursor still unidentified. Previous studies (21,22) have described a population of circulating cells, termed fibrocytes, that express fibroblast products as well as the hemopoietic stem cell Ag CD34, enter sites of tissue injury, and localize to areas of extracellular matrix deposition.…”

Section: Identification Of Circulating Fibrocytes As Precursors Of Brmentioning

confidence: 99%

“…Both these cytokines are released in excess in the airways of asthmatic patients (30, 31, 40 -42), particularly during natural or induced acute exacerbations of the disease (40,41). They are important promoters of myofibroblast differentiation in vitro (15,19,20,43,44) and are considered to play a role in the remodeling response to tissue injury by inflammation in the lung (5,45).…”

Section: Proliferation and Differentiation Of Human Fibrocytesmentioning

confidence: 99%

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Identification of Circulating Fibrocytes as Precursors of Bronchial Myofibroblasts in Asthma

Schmidt

Sun

Stacey

et al. 2003

The Journal of Immunology

579

623

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The mechanisms contributing to airway wall remodeling in asthma are under investigation to identify appropriate therapeutic targets. Bronchial myofibroblasts would represent an important target because they play a crucial role in the genesis of subepithelial fibrosis, a characteristic feature of the remodeling process, but their origin is poorly understood. We hypothesized that they originate from fibrocytes, circulating cells with the unique characteristic of expressing the hemopoietic stem cell Ag CD34 and collagen I. In this study we show that allergen exposure induces the accumulation of fibrocyte-like cells in the bronchial mucosa of patients with allergic asthma. These cells are CD34-positive; express collagen I and α-smooth muscle actin, a marker of myofibroblasts; and localize to areas of collagen deposition below the epithelium. By tracking labeled circulating fibrocytes in a mouse model of allergic asthma, we provide evidence that fibrocytes are indeed recruited into the bronchial tissue following allergen exposure and differentiate into myofibroblasts. We also show that human circulating fibrocytes acquire the myofibroblast phenotype under in vitro stimulation with fibrogenic cytokines that are produced in exaggerated quantities in asthmatic airways. These results indicate that circulating fibrocytes may function as myofibroblast precursors and may contribute to the genesis of subepithelial fibrosis in asthma.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Identification Of Circulating Fibrocytes As Precursors Of Brmentioning

confidence: 99%

Section: Identification Of Circulating Fibrocytes As Precursors Of Brmentioning

confidence: 99%

Section: Proliferation and Differentiation Of Human Fibrocytesmentioning

confidence: 99%

See 3 more Smart Citations

Identification of Circulating Fibrocytes as Precursors of Bronchial Myofibroblasts in Asthma

Schmidt

Sun

Stacey

et al. 2003

The Journal of Immunology

579

623

View full text Add to dashboard Cite

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Selective inhibition of activin receptor–like kinase 5 signaling blocks profibrotic transforming growth factor β responses in skin fibroblasts

Mori

Ishida

Bhattacharyya

et al. 2004

Arthritis & Rheumatism

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Objective. Members of the transforming growth factor ␤ (TGF␤) cytokine superfamily play critical roles in both homeostasis and disease. In light of their profibrotic effects, these molecules are implicated in the pathogenesis of fibrosis. In fibroblasts, TGF␤ signals through the activin receptor-like kinase 5 (ALK-5) type I TGF␤ and triggers Smad and MAP kinase signaling pathways. Because targeting of TGF␤ signaling represents a potential approach to the treatment of systemic sclerosis (SSc) and other fibrotic disorders, we investigated the modulation of intracellular TGF␤ signal transduction by SB431542, the first small-molecule inhibitor of ALK-5 to be described.Methods. Ligand-induced activation of the Smad signaling pathway in human dermal fibroblasts was examined by Western blot analysis and confocal immunocytochemistry. Modulation of profibrotic gene expression was investigated using Northern blot analysis, transient transfection assays, and confocal microscopy. Induction of TGF␤ production was evaluated by enzyme-linked immunosorbent assay.Results. SB431542 abrogated TGF␤-induced phosphorylation and nuclear importation of endogenous Smad2/3 and Smad4, and inhibited Smad3-and Systemic sclerosis (SSc) is a chronic disease of unknown etiology characterized by autoimmunity, vascular damage, and progressive fibrosis of the skin and internal organs. The pathogenesis of fibrosis is not well understood, and there are no effective treatments. Fibroblasts from lesional tissues show evidence of activation, with increased synthesis of collagen, fibronectin, tissue inhibitor of metalloproteinases 1 (TIMP-1), and plasminogen activator inhibitor 1 (PAI-1); secretion of profibrotic cytokines such as transforming growth factor Supported by grants from the NIH (AR-42309) and the Scleroderma Foundation.

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Elevated IL-13Rα2 in intestinal epithelial cells from ulcerative colitis or colorectal cancer initiates MAPK pathway

Mandal¹,

Levine²

2010

Inflammatory Bowel Diseases

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Chronic inflammation in ulcerative colitis (UC) is a sizeable risk factor for colorectal cancer (CRC). Interleukin-13 (IL-13) is elevated in the UC mucosa and may induce dysregulated signaling in neighboring intestinal epithelial cells (IEC) and thus function as a tumorogenic cytokine. Expression of IL-13 receptor chains on IEC obtained from control or chronically inflamed mucosa and colonic tumors was quantified by flow cytometry and immunoblot. IL-13Rα1 and IL-13Rα2 expression is significantly increased on IEC from UC and CRC patients compared to control and CD subjects. Purified IEC from these subjects and cell lines expressing varying ratios of IL-13Rα1 and α2 chains were stimulated with IL-13 in vitro to investigate by immunoblot the activation of the STAT6 and MAPK signaling pathways. Despite similarly elevated receptor expression in UC and CRC, IL-13 does not activate the STAT6 or MAPK pathways in UC, while in colonic tumors only the STAT6 pathway is activated. Using neutralizing antibodies and cell lines expressing a range of surface densities for IL-13Rα1 and IL-3Rα2, we demonstrate that IL-13Rα2 serves a dual role, initiating MAPK signaling at low concentrations and as an inhibitory, decoy receptor at high IL-13Rα2 to IL-13Rα1 ratios. Thus IL-13Rα2 is both a decoy receptor and induces MAPK signal transduction, depending on its relative expression and the local concentration of IL-13, which together modulate the balance and intensity of the signaling pathways initiated in UC and CRC.

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IL-4 and IL-13 induce myofibroblastic phenotype of human lung fibroblasts through c-Jun NH2-terminal kinase–dependent pathway

Cited by 133 publications

References 46 publications

Identification of Circulating Fibrocytes as Precursors of Bronchial Myofibroblasts in Asthma

Identification of Circulating Fibrocytes as Precursors of Bronchial Myofibroblasts in Asthma

Selective inhibition of activin receptor–like kinase 5 signaling blocks profibrotic transforming growth factor β responses in skin fibroblasts

Elevated IL-13Rα2 in intestinal epithelial cells from ulcerative colitis or colorectal cancer initiates MAPK pathway

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