Transforming growth factor-β1 downregulates vascular endothelial growth factor-D expression in human lung fibroblasts via the Jun NH2-terminal kinase signaling pathway

Ye Cui, Juan C. Osorio, Cristobal Risquez Cordovez, Hao Wang, Ying Shi, Bernadette R. Gochuico, Danielle Morse, Ivan O. Rosas, Souheil El-Chemaly

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Abstract

Vascular endothelial growth factor (VEGF)-D, a member of the VEGF family, induces both angiogenesis and lymphangiogenesis by activating VEGF receptor-2 (VEGFR-2) and VEGFR-3 on the surface of endothelial cells. Transforming growth factor (TGF)-β1 has been shown to stimulate VEGF-A expression in human lung fibroblast via the Smad3 signaling pathway and to induce VEGFC in human proximal tubular epithelial cells. However, the effects of TGF-β1 on VEGF-D regulation are unknown. To investigate the regulation of VEGF-D, human lung fibroblasts were studied under pro-fibrotic conditions in vitro and in idiopathic pulmonary fibrosis (IPF) lung tissue. We demonstrate that TGF-β1 downregulates VEGF-D expression in a dose- and time-dependent manner in human lung fibroblasts. This TGF-β1 effect can be abolished by inhibitors of TGF-β type I receptor kinase and Jun NH2-terminal kinase (JNK), but not by Smad3 knockdown. In addition, VEGF-D knockdown in human lung fibroblasts induces G1/S transition and promotes cell proliferation. Importantly, VEGF-D protein expression is decreased in lung homogenates from IPF patients compared with control lung. In IPF lung sections, fibroblastic foci show very weak VEGF-D immunoreactivity, whereas VEGF-D is abundantly expressed within alveolar interstitial cells in control lung. Taken together, our data identify a novel mechanism for downstream signal transduction induced by TGF-β1 in lung fibroblasts, through which they may mediate tissue remodeling in IPF.

Original languageEnglish (US)
Pages (from-to)120-134
Number of pages15
JournalMolecular Medicine
Volume20
Issue number1
DOIs
StatePublished - Mar 28 2014

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Vascular Endothelial Growth Factor D
JNK Mitogen-Activated Protein Kinases
Transforming Growth Factors
Down-Regulation
Fibroblasts
Lung
Idiopathic Pulmonary Fibrosis
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor-3
Lymphangiogenesis
Alveolar Epithelial Cells
Vascular Endothelial Growth Factor Receptor-2
Growth Factor Receptors
Signal Transduction
Phosphotransferases
Endothelial Cells

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Transforming growth factor-β1 downregulates vascular endothelial growth factor-D expression in human lung fibroblasts via the Jun NH2-terminal kinase signaling pathway. / Cui, Ye; Osorio, Juan C.; Risquez Cordovez, Cristobal; Wang, Hao; Shi, Ying; Gochuico, Bernadette R.; Morse, Danielle; Rosas, Ivan O.; El-Chemaly, Souheil.

In: Molecular Medicine, Vol. 20, No. 1, 28.03.2014, p. 120-134.

Research output: Contribution to journalArticle

Cui, Ye ; Osorio, Juan C. ; Risquez Cordovez, Cristobal ; Wang, Hao ; Shi, Ying ; Gochuico, Bernadette R. ; Morse, Danielle ; Rosas, Ivan O. ; El-Chemaly, Souheil. / Transforming growth factor-β1 downregulates vascular endothelial growth factor-D expression in human lung fibroblasts via the Jun NH2-terminal kinase signaling pathway. In: Molecular Medicine. 2014 ; Vol. 20, No. 1. pp. 120-134.
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