Blocking IL-17A Promotes the Resolution of Pulmonary Inflammation and Fibrosis Via TGF-β1–Dependent and –Independent Mechanisms

Mi, Su; Li, Zhe; Yang, Huiling; Liu, Hong; Wang, Jia-Ping; Ma, Yonggang; Wang, Xiaoxing; Liu, Hanzhi; Sun, Wei; Hu, Zhuowei

doi:10.4049/jimmunol.1004081

Cited by 315 publications

(287 citation statements)

References 39 publications

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“…23 Fibrosis is thought to be a result of cellular damage initiating an inflammatory response and activation of lung fibroblasts, and thus inhibition or modulation of proliferative signaling (such as TGF-b, HGF, tyrosine kinase, PDGF or PGE 2 , 9,10,24,25 which is in accordance with the increased proliferation and number of myofibroblasts presented in this paper. The specific signaling pathways of this model are still unknown, but most likely mimics the ones previously described.…”

Section: Discussionsupporting

confidence: 63%

Extracellular matrix alterations and acute inflammation; developing in parallel during early induction of pulmonary fibrosis

Rydell‐Törmänen

Andréasson

Hesselstrand

et al. 2012

Laboratory Investigation

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Pulmonary fibrosis is a hallmark of several systemic diseases such as systemic sclerosis. Initiation and early development is not well characterized, as initiation usually is unnoticed in patients, yet fibrosis has been considered a late event, occurring after an inflammatory phase. By utilizing an animal model, the starting point can be defined and the initiation process and early development thoroughly investigated. To investigate these processes from a systemic perspective, we choose a systemic administration route, instead of the more commonly used local administration. The aim of this work was to study the initiation of pulmonary fibrosis in an animal model and to investigate early alterations in connective tissue, cell turnover and acute immune response in lung parenchyma. Animals were injected subcutaneously with bleomycin, three times a week (w) for 1-4w (controls received saline). Total collagen was histologically assessed by Picro Sirius Red and Masson's Trichrome, collagen production by antibodies directed against N-terminal of procollagens I and III, proliferation by labeling with proliferating cell nuclear antigen, apoptosis by TUNEL and innate immunity by detecting neutrophils and macrophages. Total collagen was significantly increased at 1, 2 and 4w compared with controls. Procollagen I, was increased at 1w and remained increased, whereas procollagen III-staining was increased at 2w, compared with controls. Myofibroblasts were increased at all times as were proliferation, whereas apoptosis was increased from 2w. Neutrophils peaked at 1w (2779±820 cells/mm 2 ) and gradually decreased, whereas macrophages peaked at 2w (135±29 cells/mm 2 ). Subcutaneously administered bleomycin induces rapid alterations in connective tissue and cell turnover, suggesting a plasticity of the connective tissue. A transient neutrophilia is detected and increased number of macrophages likely represents a clearance process of said neutrophils. The study suggests fibrosis initiation and acute inflammation to occur in parallel in this model. (2012) 92, 917-925; Laboratory Investigation

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Section: Discussionsupporting

confidence: 63%

Extracellular matrix alterations and acute inflammation; developing in parallel during early induction of pulmonary fibrosis

Rydell‐Törmänen

Andréasson

Hesselstrand

et al. 2012

Laboratory Investigation

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“…This is further supported by the fact that neutralization of the biological activity of TGF-b ameliorates experimental liver fibrosis (2). IL-17A was reported to exhibit the ability to promote pulmonary fibrosis via TGF-b (43). In this study, we revealed IL-17RA-dependent TGF-b upregulation in CCl 4 -induced liver fibrosis.…”

Section: Discussionsupporting

confidence: 51%

IL-17A Plays a Critical Role in the Pathogenesis of Liver Fibrosis through Hepatic Stellate Cell Activation

Tan

Qian

Jiang

et al. 2013

The Journal of Immunology

260

206

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Liver fibrosis is a severe, life-threatening clinical condition resulting from nonresolving hepatitis of different origins. IL-17A is critical in inflammation, but its relation to liver fibrosis remains elusive. We find increased IL-17A expression in fibrotic livers from HBV-infected patients undergoing partial hepatectomy because of cirrhosis-related early-stage hepatocellular carcinoma in comparison with control nonfibrotic livers from uninfected patients with hepatic hemangioma. In fibrotic livers, IL-17A immunoreactivity localizes to the inflammatory infiltrate. In experimental carbon tetrachloride–induced liver fibrosis of IL-17RA–deficient mice, we observe reduced neutrophil influx, proinflammatory cytokines, hepatocellular necrosis, inflammation, and fibrosis as compared with control C57BL/6 mice. IL-17A is produced by neutrophils and T lymphocytes expressing the Th17 lineage–specific transcription factor Retinoic acid receptor–related orphan receptor γt. Furthermore, hepatic stellate cells (HSCs) isolated from naive C57BL/6 mice respond to IL-17A with increased IL-6, α-smooth muscle actin, collagen, and TGF-β mRNA expression, suggesting an IL-17A–driven fibrotic process. Pharmacologic ERK1/2 or p38 inhibition significantly attenuated IL-17A–induced HSC activation and collagen expression. In conclusion, IL-17A+ Retinoic acid receptor–related orphan receptor γt+ neutrophils and T cells are recruited into the injured liver driving a chronic, fibrotic hepatitis. IL-17A–dependent HSC activation may be critical for liver fibrosis. Thus, blockade of IL-17A could potentially benefit patients with chronic hepatitis and liver fibrosis.

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“…4). These results indicate that IL-17A induces HIBECs-EMT in vitro, consistent with the results that IL-17A can also induce EMT in alveolar and bronchial epithelial cells (Mi et al 2011;Ji et al 2013;Vittal et al 2013). These results indicated that IL-17A played a potential role in inducing EMT of IBECs and subsequent peribiliary fibrosis.…”

Section: Discussionsupporting

confidence: 79%

“…Interleukin-17 (IL-17A), a typical pro-inflammatory cytokine, has recently been shown to induce EMT of alveolar epithelial cells (Mi et al 2011) and bronchial epithelial cells (Ji et al 2013;Vittal et al 2013). Interestingly, fre-quencies of IL-17A -positive lymphocytic cells are increased in the liver of PBC patients (Lan et al 2009) and IL-17A expression is elevated in peripheral blood of PBC patients (Qian et al 2013).…”

Section: Introductionmentioning

confidence: 99%

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Interleukin-17A-Induced Epithelial-Mesenchymal Transition of Human Intrahepatic Biliary Epithelial Cells: Implications for Primary Biliary Cirrhosis

Huang

Chu

Yin

et al. 2016

Tohoku J. Exp. Med.

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Primary biliary cirrhosis (PBC) is an autoimmune chronic liver disease with worldwide increasing morbidity. However, the etiology of PBC is still unclear. Recently, the epithelial-mesenchymal transition (EMT) and interleukin-17A (IL-17A), a pro-inflammatory cytokine, were proposed to be involved in the pathogenesis of PBC. Therefore, in this study, we aimed to clarify the roles of IL-17A and/or EMT in the onset of PBC. The results showed that the median serum IL-17A level was significantly higher in 29 PBC patients (average course of 40.69 months) than that of 11 healthy controls. The intrahepatic biliary epithelial cells (IBECs), the major target of destruction in PBC, underwent EMT in PBC patients. The immunohistochemical analysis revealed that the protein levels of IL-17A receptor were increased in IBECs and the IL-17A protein was accumulated around the IBECs in the PBC patients. These results imply that the IL-17A-mediated signaling and EMT of intrahepatic biliary epithelial cells (IBEC-EMT) are key pathogenic processes of PBC. To study the association between IL-17A and IBECs-EMT, we then examined if IL-17A induced EMT using a human cell line of IBECs (HIBECs). After the treatment with IL-17A for 48 h, HIBECs changed into bipolar cells with a fibroblastic morphology. Additionally, the results of real-time PCR and Western blot analyses demonstrated that IL-17A up-regulated the expression of a mesenchymal marker vimentin and downregulated the expression of an epithelial marker E-cadherin in HIBECs in the dose-and time-dependent manners. These results suggest that IL-17A may play an important role in the IBECs-EMT.

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Blocking IL-17A Promotes the Resolution of Pulmonary Inflammation and Fibrosis Via TGF-β1–Dependent and –Independent Mechanisms

Cited by 315 publications

References 39 publications

Extracellular matrix alterations and acute inflammation; developing in parallel during early induction of pulmonary fibrosis

Extracellular matrix alterations and acute inflammation; developing in parallel during early induction of pulmonary fibrosis

IL-17A Plays a Critical Role in the Pathogenesis of Liver Fibrosis through Hepatic Stellate Cell Activation

Interleukin-17A-Induced Epithelial-Mesenchymal Transition of Human Intrahepatic Biliary Epithelial Cells: Implications for Primary Biliary Cirrhosis

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