Dickkopf proteins influence lung epithelial cell proliferation in idiopathic pulmonary fibrosis

Pfaff, E.; Becker, Sven; Güenther, Andreas; Eickelberg, Oliver; Königshoff, Mélanie

doi:10.1055/s-0029-1247942

Cited by 11 publications

(13 citation statements)

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“…8,16,37 However, it is unclear whether the increased level of Dkk1 actively modulates these inflammatory diseases or is instead a consequence of the inflammatory process. 46 Our current study suggests a profound role for elevated Dkk1 and the subsequent repression of Wnt/b-catenin signaling in the pathoprogression of acute lung inflammation by regulating ICAM-1/VCAM-1-mediated immune cell infiltration.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to Dkk1, other platelet products such as regulated on activation normal T expressed and secreted (RANTES) and CD40 ligand are found in the alveolar space. 37,58,59 Wnt3a reduces TNFa release in Mycobacterium-infected macrophages. 19 Knockdown of b-catenin in macrophages increases LPSinduced IL-6 expression.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the mRNA ( Figure 2D) and protein ( Figure 1D) expression of Dkk1 were induced in influenza virus-infected lungs. Notably, Dkk1, which was reported to accumulate in the lungs of patients with idiopathic pulmonary fibrosis, 37 was also significantly deposited in the alveoli of both the LM-challenged and the influenza virus-infected lungs ( Figure 2F). However, Dkk1 mRNA in freshly isolated AECs (data not shown) and Dkk1 protein in the BAL of the LM-challenged and influenza virus-infected lungs ( Figure 2C,E) were very low.…”

Section: Dkk1 Is Deposited In the Lungs During Acute Lung Inflammationmentioning

confidence: 96%

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Platelet-derived Wnt antagonist Dickkopf-1 is implicated in ICAM-1/VCAM-1–mediated neutrophilic acute lung inflammation

Guo

Mishra²,

Howland³

et al. 2015

Blood

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Dkk1 Is Deposited In the Lungs During Acute Lung Inflammationmentioning

confidence: 96%

See 1 more Smart Citation

Platelet-derived Wnt antagonist Dickkopf-1 is implicated in ICAM-1/VCAM-1–mediated neutrophilic acute lung inflammation

Guo

Mishra²,

Howland³

et al. 2015

Blood

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“…Dickkopf (DKK) family proteins are among 5 Wnt antagonist families, with DKK1-DKK4 being the 4 main members (15). DKK4 blocks signal transduction by binding to the Wnt co-receptor (16). As a negative feedback regulator, DKK4 plays a crucial role in regulating the Wnt/β-catenin signaling pathway; it inhibits the proliferation and invasion of colon cancer cells by blocking the canonical Wnt pathway (17).…”

Section: Introductionmentioning

confidence: 99%

High expression of the secreted protein dickkopf homolog 4: Roles in invasion and metastasis of renal cell carcinoma and its association with Von Hippel-Lindau gene

Zhai¹,

Hu²,

Zheng³

et al. 2014

International Journal of Molecular Medicine

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Abstract. The aim of this study was to investigate the effects of the dickkopf homolog 4 (DKK4)/Wnt/β-catenin signaling pathway on tumorigenesis and metastasis in clear cell renal cell carcinoma (ccRCC), as well as to elucidate the underlying mechanisms. We examined the expression of DKK4 in 30 cases of ccRCC and matched adjacent normal tissues, and investigated its correlation with clinicopathological characteristics. Stable DKK4-transfected cells were established, and DKK4 functional analyses were performed, including a T-cell factor/lymphoid enhancer factor (TCF/LEF) reporter assay, and experiments on cell viability, apoptosis, invasive capability and tumor growth in vivo. Finally, western blot analysis was performed to detect Von Hippel-Lindau (VHL) expression in 50 clinical specimens. The expression levels of the DKK4, β-catenin and β-catenin downstream target genes, cyclin D1 and c-myc, were determined in the these specimens, as well as in RCC4(-), T3-14(+) cell lines by qRT-PCR and western blot analysis. The same tests were also performed in human embryonic kidney (HEK)293 cells which were transfected with the pCDH-DKK4 plasmid. After 6 weeks the tumor weight significantly increased in the mice transfected with the tumor cells. DKK4 mRNA and protein expression levels were significantly upregulated (p<0.001). DKK4 was distinctly overexpressed (68.0%) in all patient tissues. VHL(-) samples accounted for 60.0% of all samples, while DKK4 expression was significantly upregulated in 50% of these samples, indicating a correlation with VHL(-) expression (r= 0.403, p<0.05). We also observed reduced expression levels of cyclin D1, c-myc and β-catenin (to a greater extent) in the VHL(-), RCC4(-) and T3-14(+) cells, as well as in the stably transfected HEK293 cells. DKK4 may be an oncogene, and its upregulated expression may be involved in the pathogenesis of ccRCC as a downstream gene of VHL. By activating other pathways apart from the Wnt/β-catenin pathway, DKK4 may play an important role in ccRCC tumorigenesis and metastasis.

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“…As a result of extensive epithelial regeneration and the reactivation of developmental pathways, uncontrolled fibroproliferation due to disturbed epithelial-mesenchymal crosstalk results in progressive scarring of the lung [10,11,13]. The disturbed epithelial-mesenchymal crosstalk involves: increased generation of fibrogenic mediators by the epithelium, including the tissue factor/factor VIIa-factor X complex, transforming growth factor (TGF)-β, platelet-derived growth factor (PDGF) and connective tissue growth factor [10,14]; the loss of control of fibroblasts via reduced epithelial prostaglandin E2/urokinase plasminogen activator [15]; and the upregulation of developmental pathways such as Wnt and Notch [10,13,16], which may act in a paracrine fashion on the parenchyma.…”

Section: Introductionmentioning

confidence: 99%

The role of tyrosine kinases in the pathogenesis of idiopathic pulmonary fibrosis

2015

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Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a median survival time from diagnosis of 2-3 years. Although the pathogenic pathways have not been fully elucidated, IPF is believed to be caused by persistent epithelial injury in genetically susceptible individuals. Tyrosine kinases are involved in a range of signalling pathways that are essential for cellular homeostasis. However, there is substantial evidence from in vitro studies and animal models that receptor tyrosine kinases, such as the platelet-derived growth factor receptor, vascular endothelial growth factor receptor and fibroblast growth factor receptor, and non-receptor tyrosine kinases, such as the Src family, play critical roles in the pathogenesis of pulmonary fibrosis. For example, the expression and release of tyrosine kinases are altered in patients with IPF, while specific tyrosine kinases stimulate the proliferation of lung fibroblasts in vitro. Agents that inhibit tyrosine kinases have shown anti-fibrotic and anti-inflammatory effects in animal models of pulmonary fibrosis. Recently, the tyrosine kinase inhibitor nintedanib has shown positive results in two phase III trials in patients with IPF. Here, we summarise the evidence for involvement of specific tyrosine kinases in the pathogenesis of IPF and the development of tyrosine kinase inhibitors as treatments for IPF. @ERSpublications Tyrosine kinases have been implicated in the pathogenesis of fibrosis and are a target for the treatment of IPF http://ow.ly/G71aI

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Dickkopf proteins influence lung epithelial cell proliferation in idiopathic pulmonary fibrosis

Cited by 11 publications

References 0 publications

Platelet-derived Wnt antagonist Dickkopf-1 is implicated in ICAM-1/VCAM-1–mediated neutrophilic acute lung inflammation

Platelet-derived Wnt antagonist Dickkopf-1 is implicated in ICAM-1/VCAM-1–mediated neutrophilic acute lung inflammation

High expression of the secreted protein dickkopf homolog 4: Roles in invasion and metastasis of renal cell carcinoma and its association with Von Hippel-Lindau gene

The role of tyrosine kinases in the pathogenesis of idiopathic pulmonary fibrosis

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