c-Jun N-Terminal Kinase 1 Is Required for the Development of Pulmonary Fibrosis

Alcorn, John F.; Velden, Jos van der; Brown, Amy L.; McElhinney, Brian; Irvin, Charles G.; Janssen–Heininger, Yvonne M. W.

doi:10.1165/rcmb.2008-0174oc

Cited by 86 publications

(95 citation statements)

References 75 publications

(88 reference statements)

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“…However, JNK activation was also reported recently after the stimulation of canonical Wnt signaling by Wnt3a (17). This observation, together with our finding that the absence of JNK1 protects against different murine models of lung fibrosis (18), led us to hypothesize that the JNK activation induced by canonical Wnt/b-catenin is important in the induction of a mesenchymal expression profile in lung epithelial cells. Therefore, this study was designed to investigate the possible role of the Wnt signaling pathway in inducing EMT in lung epithelial cells, and to unravel the role of JNK1 therein.…”

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confidence: 79%

Induction of a Mesenchymal Expression Program in Lung Epithelial Cells by Wingless Protein (Wnt)/β-Catenin Requires the Presence of c-Jun N-Terminal Kinase–1 (JNK1)

Velden

Guala

Leggett

et al. 2012

Am J Respir Cell Mol Biol

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Recent studies suggest the importance of the transition of airway epithelial cells (EMT) in pulmonary fibrosis, and also indicate a role for Wingless protein (Wnt)/b-catenin signaling in idiopathic pulmonary fibrosis. We investigated the possible role of the Wnt signaling pathway in inducing EMT in lung epithelial cells, and sought to unravel the role of c-Jun-N-terminal-kinase-1 (JNK1). The exposure of C10 lung epithelial cells or primary mouse tracheal epithelial cells (MTECs) to Wnt3a resulted in increases in JNK phosphorylation and nuclear b-catenin content. Because the role of b-catenin as a transcriptional coactivator is well established, we investigated T-cell factor/lymphocyteenhancement factor (TCF/LEF) transcriptional activity in C10 lung epithelial cells after the activation of Wnt. TCF/LEF transcriptional activity was enhanced after the activation of Wnt, and this increase in TCF/LEF transcriptional activity was diminished after the small interfering (si)RNA-mediated ablation of JNK. The activation of the Wnt pathway by Wnt3a, or the expression of either wild-type or constitutively active b-catenin (S37A), led to the activation of an EMT transcriptome, manifested by the increased mRNA expression of CArG box-binding factor-A, fibroblast-specific protein (FSP)-1, a-smooth muscle actin (a-SMA), and vimentin, increases in the content of a-SMA and FSP1, and the concomitant loss of zona occludens-1. The siRNA-mediated ablation of b-catenin substantially decreased Wnt3a-induced EMT. The siRNA ablation of JNK1 largely abolished Wnt3a, b-catenin, and b-catenin S37a-induced EMT. In MTECs lacking Jnk1, Wnt3a-induced increases in nuclear b-catenin, EMT transcriptome, and the content of a-SMA or FSP1 were substantially diminished. These data show that the activation of the Wnt signaling pathway is capable of inducing an EMT program in lung epithelial cells through b-catenin, and that this process is controlled by JNK1.Keywords: lung; epithelium; Wnt3a; fibrosis; epithelial to mesenchymal transitionThe development of fibrosis represents an important feature of pulmonary remodeling, and the critical role of epithelial cells in fibrogenesis is emerging. Studies from our laboratory identified a critical role for c-Jun-N-terminal-kinase-1 (JNK1) in augmenting the profibrotic effects of TGF-b1, in association with the causation of a mesenchymal transition of airway epithelialcells (EMT) (1). EMT is an important process during embryonic development, tumor progression, and fibrotic tissue repair after injury (2). We recently demonstrated that JNK1-induced phosphorylation in the linker domain of SMAD3 enhanced its ability to induce an EMT transcriptome. Consequently, JNK1-dependent, TGF-b1-induced EMT was greatly diminished in epithelial cells expressing a variant of SMAD3 refractory to phosphorylation in the linker domain (3).Recent studies indicated a role of b-catenin signaling in the induction of EMT. Moreover, the Wingless protein (Wnt)/ b-catenin axis was recently implicated to play a role in the development of idio...

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confidence: 79%

Induction of a Mesenchymal Expression Program in Lung Epithelial Cells by Wingless Protein (Wnt)/β-Catenin Requires the Presence of c-Jun N-Terminal Kinase–1 (JNK1)

Velden

Guala

Leggett

et al. 2012

Am J Respir Cell Mol Biol

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“…Because TNF-a is found to be increased in sputum of patients with stable COPD, this could be associated with the increased activation of JNK in these patients (30). The data from SPC-TNF-a mice in this study are in line with a study showing that mice lacking JNK1 are protected against TGF-b-induced pulmonary fibrosis and fibrotic gene expression (31,32). This is also supported by another study showing that JNK knockout mice were found to have an increased pulmonary elastin content compared with wild-type mice, and showed increased elastogenesis, but had impaired alveolar septation during lung development (33).…”

Section: Discussionsupporting

confidence: 86%

Involvement of c-Jun N-Terminal Kinase in TNF-α–Driven Remodeling

Eurlings

Reynaert

Wetering

et al. 2017

Am J Respir Cell Mol Biol

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Lung tissue remodeling in chronic obstructive pulmonary disease (COPD) is characterized by airway wall thickening and/or emphysema. Although the bronchial and alveolar compartments are functionally independent entities, we recently showed comparable alterations in matrix composition comprised of decreased elastin content and increased collagen and hyaluronan contents of alveolar and small airway walls. Out of several animal models tested, surfactant protein C (SPC)-TNF-a mice showed remodeling in alveolar and airway walls similar to what we observed in patients with COPD. Epithelial cells are able to undergo a phenotypic shift, gaining mesenchymal properties, a process in which c-Jun N-terminal kinase (JNK) signaling is involved. Therefore, we hypothesized that TNF-a induces JNK-dependent epithelial plasticity, which contributes to lung matrix remodeling. To this end, the ability of TNF-a to induce a phenotypic shift was assessed in A549, BEAS2B, and primary bronchial epithelial cells, and phenotypic markers were studied in SPC-TNF-a mice. Phenotypic markers of mesenchymal cells were elevated both in vitro and in vivo, as shown by the expression of vimentin, plasminogen activator inhibitor-1, collagen, and matrix metalloproteinases. Concurrently, the expression of the epithelial markers, E-cadherin and keratin 7 and 18, was attenuated. A pharmacological inhibitor of JNK attenuated this phenotypic shift in vitro, demonstrating involvement of JNK signaling in this process. Interestingly, activation of JNK signaling was also clearly present in lungs of SPC-TNF-a mice and patients with COPD. Together, these data show a role for TNF-a in the induction of a phenotypic shift in vitro, resulting in increased collagen production and the expression of elastin-degrading matrix metalloproteinases, and provide evidence for involvement of the TNF-a-JNK axis in extracellular matrix remodeling.

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“…Broad varieties of stress stimulate JNK activation and in turn phosphorylate several transcription factors, such as c-Jun, JunB, and ATF-2, required for cell survival, proliferation, transformation, and death ( 8,9 ). Previous observations suggest a potential role for JNK in allergic airway diseases and fi brosis and show that the phosphorylation of JNK is elevated in the airway epithelium and pulmonary endothelium of patients with idiopathic pulmonary fi brosis ( 10 ). However, the linkage among JNK, pulmonary hypertension, and endothelium growth requires more study.…”

Section: Immunocytochemistrymentioning

confidence: 99%