Cyclic phosphatidic acid influences the expression and regulation of cyclic nucleotide phosphodiesterase 3B and lipolysis in 3T3-L1 cells |
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Authors: | Tsukahara Tamotsu Hanazawa Shuwa Murakami-Murofushi Kimiko |
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Affiliation: | aDepartment of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, Japan;bResearch Institute for Diseases of Old Ages, Juntendo University School of Medicine, Tokyo, Japan;cDepartment of Immunology, Juntendo University School of Medicine, Tokyo, Japan;dAtopy (Allergy) Research Center, Juntendo University School of Medicine, Tokyo, Japan;eDepartment of Ophthalmology, Tokyo Medical University, Tokyo, Japan;fUBC James Hogg Research Centre, Providence Heart + Lung Institute, University of British Columbia, Vancouver, British Columbia, Canada |
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Abstract: | The abundance of transforming growth factor-beta (TGF-β) in normal airway epithelium suggests its participation in physiological processes to maintain airway homeostasis. The current study was designed to address the hypothesis that TGF-β1 and TGF-β2 might contribute to normal reparative response of airway epithelial cells (AECs). Treatments with exogenous TGF-β1 or TGF-β2 significantly enhanced wound repair of confluent AEC monolayers. Mechanical injury of AEC monolayers induced production of both TGF-β1 and TGF-β2. Wound repair of AECs was significantly reduced by a specific inhibitor of TGF-β type I receptor kinase activity. We investigated whether the TGF-β-enhanced repair required epidermal growth factor receptor (EGFR) transactivation and secretion of EGFR ligands. Both TGF-β1 and TGF-β2 enhanced EGFR phosphorylation and induced production of heparin-binding EGF-like growth factor (HB-EGF) and transforming growth factor-alpha (TGF-α) in AECs. Moreover, treatment with a broad-spectrum metalloproteinase inhibitor or anti-HB-EGF and anti-TGF-α antibodies inhibited the wound repair and the EGFR phosphorylation by TGF-β1 and TGF-β2, indicating that the TGF-β1 and TGF-β2 effects on wound repair required the release of HB-EGF and TGF-α. Our data, for the first time, have shown that both TGF-β1 and TGF-β2 play a stimulatory role in airway epithelial repair through EGFR phosphorylation following autocrine production of HB-EGF and TGF-α. These findings highlight an important collaborative mechanism between TGF-β and EGFR in maintaining airway epithelial homeostasis. |
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Keywords: | Bronchial epithelial cell Epithelial repair Transforming growth factor-beta Heparin-binding EGF-like growth factor Transforming growth factor-alpha |
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