Endothelin-1 induces VCAM-1 expression-mediated inflammation via receptor tyrosine kinases and Elk/p300 in human tracheal smooth muscle cells.

Abstract

The elevated level of endothelin-1 (ET-1) has been detected in the bronchoalveolar lavage of patients with severe asthma, acute lung injury, acute respiratory distress syndrome, and sepsis. ET-1 may affect vessel tone together with lung physiology and pathology. Vascular cell adhesion molecule-1 (VCAM-1) is one kind of adhesion molecules participating in the process of polymorphonuclear leukocyte transmigration and regulating the occurrence and amplification of tissue inflammation. However, the molecular mechanisms underlying ET-1-mediated expression of VCAM-1 on human tracheal smooth muscle cells (HTSMCs) were largely unknown. Here we reported that ET-1 stimulated expression of VCAM-1 gene on HTSMCs, which was blocked by pretreatment with the inhibitors of ET receptors, Src, matrix metalloproteinases (MMPs), epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), phosphatidylinositol 3-kinase (PI3K), AKT, MEK1/2, and p300, suggesting the participation of these signaling components in ET-1-regulated HTSMC responses. Furthermore, transfection with small-interfering RNA (siRNA) of Src, AKT, p42 mitogen-activated protein kinase (MAPK), or p300 downregulated the respective proteins and significantly attenuated ET-1-induced VCAM-1 expression. ET-1 also stimulated phosphorylation of Src, EGFR, PDGFR, AKT, p42/p44 MAPK, and Elk-1 and acetylation of histone H4 on HTSMCs. Immunoprecipitation assay showed the association between Elk-1 and p300 in the nucleus. Adhesion assay revealed that the adhesion of THP-1 to HTSMCs challenged with ET-1 was increased, which was attenuated by the inhibitors of ET receptors, Src, MMPs, EGFR, PDGFR, PI3K, AKT, p42/p44 MAPK, and p300. Taken together, these data suggested that ET-1 promotes occurrence and amplification of pathology-related airway inflammation via enhancing VCAM-1 expression in an ET receptor/Src/MMP/EGFR, PDGFR/PI3K/AKT/p42/p44 MAPK/Elk-1/p300 pathway in HTSMCs.

• Authors: Chih-Chung Lin, Wei-Ning Lin, Wei-Chen Hou, Li-Der Hsiao, Chuen-Mao Yang
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 309 Issue 3 Pg. L211-25 (Aug 01 2015) ISSN: 1522-1504 [Electronic] United States
• PMID: 26071554 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 the American Physiological Society.

Chemical References

• ELK1 protein, human
• Endothelin-1
• Receptors, G-Protein-Coupled
• Vascular Cell Adhesion Molecule-1
• ets-Domain Protein Elk-1
• p300-CBP Transcription Factors
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinase 1
• MMP2 protein, human
• Matrix Metalloproteinase 2
• MMP9 protein, human
• Matrix Metalloproteinase 9

Topics

• Acetylation
• Asthma (immunology, metabolism, pathology)
• Cells, Cultured
• Endothelin-1 (physiology)
• Gene Expression
• Humans
• MAP Kinase Signaling System
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Myocytes, Smooth Muscle (immunology, metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Protein Processing, Post-Translational
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptors, G-Protein-Coupled (metabolism)
• Trachea (pathology)
• Transcriptional Activation
• Vascular Cell Adhesion Molecule-1 (genetics, metabolism)
• ets-Domain Protein Elk-1 (metabolism)
• p300-CBP Transcription Factors (metabolism)