Endothelin-1 induces expression of matrix-associated genes in lung fibroblasts through MEK/ERK.
The endothelins are a family of endothelium-derived peptides that possess a variety of biological activities, including potent vasoconstriction. Endothelin-1 (ET-1) is up-regulated during tissue repair and pulmonary fibrosis. Here, we use genome-wide expression array analysis to show that the addition of ET-1 (100 nm, 4 h) to normal lung fibroblasts directly induces expression of matrix and matrix-associated genes, including the profibrotic protein CCN2 (connective tissue growth factor, or CTGF). ET-1 induces the MEK/ERK MAP kinase pathway in fibroblasts. Blockade of the MEK/ERK kinase pathway with U0126 abrogates the ability of ET-1 to induce expression of matrix and matrix-associated mRNAs and the CCN2 protein. The CCN2 promoter possesses an ET-1 response element, which maps to the previously identified basal control element-1 (BCE-1) site. Our results suggest that ET-1 induces a program of matrix synthesis in lung fibroblasts and that ET-1 may play a key role in connective tissue deposition during wound repair and in pulmonary fibrosis.
Xu
Shi-wen
SW
Centre for Rheumatology, Department of Medicine, Royal Free and University College London, United Kingdom.
Howat
Sarah L
SL
Renzoni
Elisabetta A
EA
Holmes
Alan
A
Pearson
Jeremy D
JD
Dashwood
Michael R
MR
Bou-Gharios
George
G
Denton
Christopher P
CP
du Bois
Roland M
RM
Black
Carol M
CM
Leask
Andrew
A
Abraham
David J
DJ
D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008168:Lung / Q000166:cytology / Q000378:metabolism; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
D019332:Endothelin-1; D016326:Extracellular Matrix Proteins; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; C482576:MAP3K1 protein, human